Aryloazol-2-yl cyanoethylamino compounds, method of making and method of using thereof

ABSTRACT

The present invention relates to novel aryloazol-2-yl-cyanoethylamino derivatives of formula (I): 
                         
wherein R 3 , R 4 , R 5 , R 6 , R 7 , P, Q, V, W, X, Y, Z and a are as defined in the description, compositions thereof, processes for their preparation and their uses as pesticides.

INCORPORATION BY REFERENCE

This application is a continuation of U.S. patent application Ser. No.13/325,467 filed on Dec. 14, 2011, now U.S. Pat. No. 8,283,475; which isa continuation of U.S. patent application Ser. No. 12/119,150 filed May12, 2008, now U.S. Pat. No. 8,088,801; which claims priority to U.S.Provisional Application No. 60/930,485, filed May 15, 2007.

Any foregoing applications and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

FIELD OF THE INVENTION

The present invention relates to novel aryloazol-2-yl-cyanoethylaminoderivatives of formula (I):

wherein, R₃, R₄, R₅, R₆, R₇, P, Q, V, W, X, Y, Z, and a are as definedin the description, compositions thereof, processes for theirpreparation and their uses as pesticides.

BACKGROUND OF THE INVENTION

The control of parasites, particularly endoparasites which parasitizeanimals, by means of active material having a cyanoethylamino group hasbeen described by many patents or patent application such asInternational Patent Publications No. WO 2004/024704 (U.S. Pat. No.7,084,280), WO 2005/044784, WO 2005/121075 and WO 2006/043654 as well asin EP 953565 (U.S. Pat. No. 6,239,077) and EP 1445251.

However none of the foregoing publications describe that compounds offormula (I) possess activity as pesticides, particularly for controllingendoparasitic pests in or on animals and ectoparasitic pests on animals.

OBJECTS AND SUMMARY OF THE INVENTION

This invention provides novel arylo-azol-2-yl-cyanoethylaminoderivatives of the formula (I):

-   P is C—R₁ or N;-   Q is C—R₂ or N;-   V is C—R₈ or N;-   W is C—R₉ or N;-   X is C—R₁₀ or N;-   Y is C—R₁₁ or N;-   R₁, R₂, R₈, R₉, R₁₀ and R₁₁ either together or independently of one    another, are hydrogen, amino, amido, cyano, nitro, halogen, alkyl,    alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, phenoxy, alkoxyalkoxy,    cycloalkyloxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl,    alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, alkylamino,    di(alkyl)amino, alkylcarbonylamino, alkylaminoalkoxy,    dialkylaminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl,    formyl, HO₂C—, alkyl-O₂C—, unsubstituted or substituted aryl or    unsubstituted or substituted phenoxy, whereby the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    haloalkylsulfonyl;-   R₃, R₄ and R₅ either together or independently of one another, are    hydrogen, halogen, alkyl, hydroxyalkyl, alkylthioalkyl, haloalkyl,    alkyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,    alkylsulfonyloxyalkyl; unsubstituted or substituted cycloalkyl,    wherein the substituents may each be independent of one another and    are selected from the group consisting of halogen and alkyl;    unsubstituted or substituted phenyl, whereby the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    haloalkylsulfonyl, alkylamino, di(alkyl)amino; or-   R₄ and R₅ together with the carbon to which they are attached form a    cycloalkyl ring;-   R₆ is hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylthiocarbonyl    or unsubstituted or substituted benzyl, whereby the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    haloalkylsulfonyl, alkylamino, di(alkyl)amino;-   R₇ is hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylthiocarbonyl    or unsubstituted or substituted phenyl wherein the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, phenyl,    phenoxy, alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy,    alkylcarbonyl, haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl,    alkylsulfonyl, haloalkylsulfonyl alkylamino, di(alkyl)amino;    unsubstituted or substituted hetaryl, wherein the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    alkylamino, di(alkyl)amino;    -   or    -   unsubstituted or substituted naphthyl or quinolyl, wherein the        substituents may each be independent of one another and are        selected from the group consisting of cyano, nitro, halogen,        alkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy,        haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkylsulfinyl,        haloalkylsulfinyl, alkylsulfonyl, alkylamino, di(alkyl)amino;-   Z is a direct bond, C(O), C(S) or S(O)_(p);-   a is 1, 2 or 3;-   p is 0, 1 or 2.

It is an object of the present invention to provide new pesticidalcompounds of the aryloazol-2-yl-cyanoethylamino family together withprocesses for their preparation.

A second object of the present invention is to provide pesticidalcompositions and pesticidal methods of use of the pesticidalaryloazol-2-yl-cyanoethylamino in the field of pest control which arewell tolerated by warm-blooded species, fish and plants, including inparticular for controlling endo- and ectoparasites which parasitizemammals, fish and birds.

Another object of the present invention is to provide compounds withhigh activity and improved safety to the user and the environment, whichare obtained by optimization of chemical, physical and biologicalproperties such as solubility, melting point, stability, electronic andsteric parameters, and the like.

For the purposes of this application, unless otherwise stated in thespecification, the following terms have the definitions cited below:

(1) Alkyl refers to both straight and branched carbon chains; referencesto individual alkyl groups are specific for the straight chain (e.g.butyl=n-butyl). In one embodiment of alkyl, the number of carbons atomsis 1-20, in another embodiment of alkyl, the number of carbon atoms is1-8 carbon atoms and in yet another embodiment of alkyl, the number ofcarbon atoms is 1-4 carbon atoms. Other ranges of carbon numbers arealso contemplated depending on the location of the alkyl moiety on themolecule;(2) Alkenyl refers to both straight and branched carbon chains whichhave at least one carbon-carbon double bond. In one embodiment ofalkenyl, the number of double bonds is 1-3, in another embodiment ofalkenyl, the number of double bonds is one. In one embodiment ofalkenyl, the number of carbons atoms is 2-20, in another embodiment ofalkenyl, the number of carbon atoms is 2-8 and in yet another embodimentof alkenyl, the number of carbon atoms is 2-4. Other ranges ofcarbon-carbon double bonds and carbon numbers are also contemplateddepending on the location of the alkenyl moiety on the molecule;(3) Alkynyl refers to both straight and branched carbon chains whichhave at least one carbon-carbon triple bond. In one embodiment ofalkynyl, the number of triple bonds is 1-3; in another embodiment ofalkynyl, the number of triple bonds is one. In one embodiment ofalkynyl, the number of carbons atoms is 2-20, in another embodiment ofalkynyl, the number of carbon atoms is 2-8 and in yet another embodimentof alkynyl, the number of carbon atoms is 2-4. Other ranges ofcarbon-carbon double bonds and carbon numbers are also contemplateddepending on the location of the alkenyl moiety on the molecule;(4) Aryl refers to a C₆-C₁₀ aromatic ring structure. In one embodimentof aryl, the moiety is phenyl, naphthyl, tetrahydronapthyl,phenylcyclopropyl and indanyl; in another embodiment of aryl, the moietyis phenyl. Arylo refers to an aryl substituted at two adjacent sites.(5) Alkoxy refers to —O-alkyl, wherein alkyl is as defined in (1);(6) Alkanoyl refers to formyl (—C(═O)H) and —C(═O)-alkyl, wherein alkylis as defined in (1);(7) Alkanoyloxy refers to —O—C(═O)-alkyl, wherein alkanoyl is as definedin (6);(8) Alkanoylamino refers to —NH₂—C(═O)-alkyl, wherein alkanoyl is asdefined in (6) and the amino (NH₂) moiety can be substituted by alkyl asdefined in (1);(9) Aminocarbonyl refers to —NH₂—C(═O), wherein the amino (NH₂) moietycan be substituted by alkyl as defined in (1);(10) Alkoxycarbonyl refers to —C(═O)—O-alkyl, wherein alkoxy is asdefined in (5);(11) Alkenoyl refers to —C(═O)-alkenyl, wherein alkenyl is as defined in(2);(12) Alkynoyl refers to —C(═O)-alkynyl, wherein alkynyl is as defined in(3);(13) Aroyl refers to —C(═O)-aryl, wherein aryl is as defined above;(14) Cyclo as a prefix (e.g. cycloalkyl, cycloalkenyl, cycloalkynyl)refers to a saturated or unsaturated cyclic ring structure having fromthree to eight carbon atoms in the ring the scope of which is intendedto be separate and distinct from the definition of aryl above. In oneembodiment of cyclo, the range of ring sizes is 4-7 carbon atoms; inanother embodiment of cyclo the range of ring sizes is 3-4. Other rangesof carbon numbers are also contemplated depending on the location of thecyclo-moiety on the molecule;(15) Halogen means the atoms fluorine, chlorine, bromine and iodine. Thedesignation of “halo” (e.g. as illustrated in the term haloalkyl) refersto all degrees of substitutions from a single substitution to a perhalosubstitution (e.g. as illustrated with methyl as chloromethyl (—CH₂Cl),dichloromethyl (—CHCl₂), trichloromethyl (—CCl₃));(16) Heterocycle, heterocyclic or heterocyclo refer to fully saturatedor unsaturated, including aromatic (i.e. “hetaryl”) cyclic groups, forexample, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to15 membered tricyclic ring systems, which have at least one heteroatomin at least one carbon atom-containing ring. Each ring of theheterocyclic group containing a heteroatom may have 1, 2, 3 or 4heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfuratoms, where the nitrogen and sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom ofthe ring or ring system.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

Unless otherwise specifically noted or apparent by context, “activeagent” or “active ingredient” or “therapeutic agent” as used in thisspecification, means an arylo-azol-2-yl-cyanoethylamino compound of theinvention.

The compounds of the invention are intended to encompass racemicmixtures, specific stereoisomers and tautomeric forms of the compound.Another aspect of the invention is a salt form of the compound of theinvention.

Another aspect of the invention are solid state forms of the compoundsof the invention which consists of crystalline forms selected from thegroup consisting of single crystals, nanocrystals, co-crystals,molecular complexes, hydrates, anhydrates, solvates, desolvates,clathrates and inclusion complexes and non-crystalline forms selectedfrom the group consisting of non-crystalline glass and non-crystallineamorphous forms.

It is further noted that the invention does not intend to encompasswithin the scope of the invention any previously disclosed product,process of making the product or method of using the product, whichmeets the written description and enablement requirements of the USPTO(35 U.S.C. 112, first paragraph) or the EPO (Article 83 of the EPC),such that applicant(s) reserve the right and hereby disclose adisclaimer of any previously described product, method of making theproduct or process of using the product.

It is noted that in this disclosure and particularly in the claimsand/or paragraphs, terms such as “comprises”, “comprised”, “comprising”and the like can have the meaning attributed to it in U.S. patent law;e.g., they can mean “includes”, “included”, “including”, and the like;and that terms such as “consisting essentially of” and “consistsessentially of” have the meaning ascribed to them in U.S. patent law,e.g., they allow for elements not explicitly recited, but excludeelements that are found in the prior art or that affect a basic or novelcharacteristic of the invention.

These and other embodiments are disclosed or are apparent from andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention provides novelaryloazol-2-yl-cyanoethylamino derivatives of the formula (I):

wherein:

-   P is C—R₁ or N;-   Q is C—R₂ or N;-   V is C—R₈ or N;-   W is C—R₉ or N;-   X is C—R₁₀ or N;-   Y is C—R₁₁ or N;-   R₁, R₂, R₈, R₉, R₁₀ and R₁₁ either together or independently of one    another, are hydrogen, amino, amido, cyano, nitro, halogen, alkyl,    alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, phenoxy, alkoxyalkoxy,    cycloalkyloxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl,    alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, alkylamino,    di(alkyl)amino, alkylcarbonylamino, alkylaminoalkoxy,    dialkylaminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl,    formyl, HO₂C—, alkyl-O₂C—, unsubstituted or substituted aryl or    unsubstituted or substituted phenoxy, whereby the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    haloalkylsulfonyl;-   R₃, R₄ and R₅ either together or independently of one another, are    hydrogen, halogen, alkyl, hydroxyalkyl, alkylthioalkyl, haloalkyl,    alkyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,    alkylsulfonyloxyalkyl; unsubstituted or substituted cycloalkyl,    wherein the substituents may each be independent of one another and    are selected from the group consisting of halogen and alkyl;    unsubstituted or substituted phenyl, whereby the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    haloalkylsulfonyl, alkylamino, di(alkyl)amino; or-   R₄ and R₅ together with the carbon to which they are attached form a    cycloalkyl ring;-   R₆ is hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylthiocarbonyl    or unsubstituted or substituted benzyl, whereby the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    haloalkylsulfonyl, alkylamino, di(alkyl)amino;-   R₇ is hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylthiocarbonyl    or unsubstituted or substituted phenyl wherein the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, phenyl,    phenoxy, alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy,    alkylcarbonyl, haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl,    alkylsulfonyl, haloalkylsulfonyl alkylamino, di(alkyl)amino;    unsubstituted or substituted hetaryl, wherein the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio,    haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,    haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,    alkylamino, di(alkyl)amino;    -   or    -   unsubstituted or substituted naphthyl or quinolyl, wherein the        substituents may each be independent of one another and are        selected from the group consisting of cyano, nitro, halogen,        alkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy,        haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkylsulfinyl,        haloalkylsulfinyl, alkylsulfonyl, alkylamino, di(alkyl)amino;-   Z is a direct bond, C(O), C(S) or S(O)_(p);-   a is 1, 2 or 3; and-   p is 0, 1 or 2.

In one embodiment of the first aspect of the invention provides a novelaryloazol-2-yl-cyanoethylamino derivatives of the formula (I), wherein

-   P is C—R₁ or N;-   Q is C—R₂ or N;-   V is C—R₈ or N;-   W is C—R₉ or N;-   X is C—R₁₀ or N;-   Y is C—R₁₁ or N;-   R₁, R₂, R₈, R₉, R₁₀ and R₁₁ either together or independently of one    another, are hydrogen, amino, amido, cyano, nitro, halogen,    C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl,    hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio arylthio, C₁-C₆-alkoxy, phenoxy,    C₁-C₆-alkoxy-C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, halo-C₁-C₆-alkoxy,    C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆ alkylamino,    di(C₁-C₆-alkyl)amino, C₁-C₆-alkylcarboxylamino,    C₁-C₆-alkylamino-C₁-C₆-alkoxy, di-C₁-C₆-alkylamino-C₁-C₆-alkoxy,    C₁-C₆-alkylamino-C₁-C₆-alkyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl,    amino-C₁-C₆-alkyl, formyl, HO₂C—, C₁-C₆-alkyl-O₂C—, unsubstituted or    substituted aryl or unsubstituted or substituted phenoxy, whereby    the substituents may each be independent of one another and are    selected from the group consisting of cyano, nitro, halogen,    C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,    C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆ alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl;-   R₃, R₄ and R₅ either together or independently of one another, are    hydrogen, halogen, C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,    C₁-C₆-alkylthio-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,    C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl,    C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyloxy-C₁-C₆-alkyl;    unsubstituted or substituted C₃-C₇-cycloalkyl, wherein the    substituents may each be independent of one another and are selected    from the group consisting of halogen and C₁-C₆-alkyl; unsubstituted    or substituted phenyl, whereby the substituents may each be    independent of one another and are selected from the group    consisting of cyano, nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,    C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,    C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino; or-   R₄ and R₅ together with the carbon to which they are attached form a    cycloalkyl ring;-   R₆ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkylthiocarbonyl or unsubstituted or    substituted benzyl, whereby the substituents may each be independent    of one another and are selected from the group consisting of cyano,    nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,    C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;-   R₇ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkylthiocarbonyl or unsubstituted or    substituted phenyl wherein the substituents may each be independent    of one another and are selected from the group consisting of cyano,    nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, phenyl, phenoxy,    C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,    C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;    unsubstituted or substituted hetaryl, wherein the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,    C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,    C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;    -   or    -   unsubstituted or substituted naphthyl or quinolyl, wherein the        substituents may each be independent of one another and are        selected from the group consisting of cyano, nitro, halogen,        C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,        halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,        C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,        C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,        C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;-   Z is a direct bond, C(O), C(S) or S(O)_(p);-   a is 1, 2 or 3; and-   p is 0, 1 or 2.

In another embodiment of the first aspect of the invention, compounds offormula (I) above are compounds wherein:

-   P and Q are N;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₃, R₄ and R₆ are H;-   R₈, R₉, R₁₀ and R₁₁ either together or independently of one another,    are hydrogen, amino, amido, cyano, nitro, halogen, C₁-C₆-alkyl,    C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, hydroxy-C₁-C₆-alkyl,    halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio arylthio,    C₁-C₆-alkoxy, phenoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy,    C₃-C₇-cycloalkyloxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino,    di(C₁-C₆-alkyl)amino, C₁-C₆-alkylcarboxylamino,    C₁-C₆-alkylamino-C₁-C₆-alkoxy, di-C₁-C₆-alkylamino-C₁-C₆-alkoxy,    C₁-C₆-alkylamino-C₁-C₆-alkyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl,    amino-C₁-C₆-alkyl, formyl, HO₂O—, C₁-C₆-alkyl-O₂O—, unsubstituted or    substituted aryl or unsubstituted or substituted phenoxy, whereby    the substituents may each be independent of one another and are    selected from the group consisting of cyano, nitro, halogen,    C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,    C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl;-   R₅ is methyl or C₁-C₃-alkyl;-   R₇ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkylthiocarbonyl or unsubstituted or    substituted phenyl wherein the substituents may each be independent    of one another and are selected from the group consisting of cyano,    nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, phenyl, phenoxy,    C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,    C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;    unsubstituted or substituted hetaryl, wherein the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,    C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,    C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;    -   or    -   unsubstituted or substituted naphthyl or quinolyl, wherein the        substituents may each be independent of one another and are        selected from the group consisting of cyano, nitro, halogen,        C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,        halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,        C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,        C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,        C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;-   Z is a direct bond, C(O), C(S) or S(O)_(p);-   a is 1;-   p is 0 or 1.

In yet another embodiment of the first aspect of the invention,compounds of formula (I) above are compounds wherein:

-   P and Q is N;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₈, R₉, R₁₀ and R₁₁ either together or independently of one another,    are hydrogen, amino, amido, cyano, nitro, halogen, C₁-C₆-alkyl,    C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, hydroxy-C₁-C₆-alkyl,    halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio arylthio,    C₁-C₆-alkoxy, phenoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy,    C₃-C₇-cycloalkyloxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino,    di(C₁-C₆-alkyl)amino, C₁-C₆-alkylcarboxylamino,    C₁-C₆-alkylamino-C₁-C₆-alkoxy, di-C₁-C₆-alkylamino-C₁-C₆-alkoxy,    C₁-C₆-alkylamino-C₁-C₆-alkyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl,    amino-C₁-C₆-alkyl, formyl, HO₂C—, C₁-C₆-alkyl-O₂C—, unsubstituted or    substituted aryl or unsubstituted or substituted phenoxy, whereby    the substituents may each be independent of one another and are    selected from the group consisting of cyano, nitro, halogen,    C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,    C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl;-   R₃, R₄ and R₆ are H;-   R₅ is methyl or C₁-C₃-alkyl;-   R₇ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,    C₁-C₆-alkylcarbonyl, C₁-C₆-alkylthiocarbonyl or unsubstituted or    substituted phenyl wherein the substituents may each be independent    of one another and are selected from the group consisting of cyano,    nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, phenyl, phenoxy,    C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,    C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;    unsubstituted or substituted hetaryl, wherein the substituents may    each be independent of one another and are selected from the group    consisting of cyano, nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,    C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,    C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino;-   Z is C(O); and-   a is 1.

In still another embodiment of the first aspect of the invention,compounds of formula (I) above are compounds wherein:

-   P and Q are N;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₈, R₉, R₁₀ and R₁₁ either together or independently of one another,    are hydrogen, amino, amido, cyano, nitro, halogen, C₁-C₆-alkyl,    C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, hydroxy-C₁-C₆-alkyl,    halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio arylthio,    C₁-C₆-alkoxy, phenoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy,    C₃-C₇-cycloalkyloxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino,    di(C₁-C₆-alkyl)amino, C₁-C₆-alkylcarboxylamino,    C₁-C₆-alkylamino-C₁-C₆-alkoxy, di-C₁-C₆-alkylamino-C₁-C₆-alkoxy,    C₁-C₆-alkylamino-C₁-C₆-alkyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl,    amino-C₁-C₆-alkyl, formyl, HO₂O—, C₁-C₆-alkyl-O₂O—, unsubstituted or    substituted aryl or unsubstituted or substituted phenoxy, whereby    the substituents may each be independent of one another and are    selected from the group consisting of cyano, nitro, halogen,    C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,    C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,    halo-C₁-C₆-alkylsulfonyl;-   R₃, R₄ and R₆ are H;-   R₅ is methyl-   R₇ is unsubstituted or substituted phenyl wherein the substituents    may each be independent of one another and are selected from the    group consisting of cyano, nitro, halogen, C₁-C₆-alkyl,    halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio,    C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino,    di(C₁-C₆-alkyl)amino; unsubstituted or substituted hetaryl, wherein    the substituents may each be independent of one another and are    selected from the group consisting of cyano, nitro, halogen,    C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,    C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,    halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino,    di(C₁-C₆-alkyl)amino;-   Z is C(O); and-   a is 1.

In still another embodiment of the first aspect of the invention,compounds of formula (I) above are compounds wherein:

-   P and Q are N;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkylthioalkyl,    alkyloxyalkyl, or alkylsulfonyloxyalkyl;-   R₇ is unsubstituted phenyl or phenyl substituted by one or more    substituents selected from the group consisting of alkyl, haloalkyl,    phenyl, phenyloxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,    haloalkylsulfinyl and haloalkylsulfonyl;-   R₈, R₉, R₁₀ and R₁₁ either together or independently of one another,    are hydrogen, halogen, alkyl, haloalkyl, cyano, alkoxy, haloalkoxy,    alkenyl, alkylamino, hydroxyalkyl, formyl, alkylaminoalkyl,    dialkylaminoalkyl, aminoalkyl, HO₂C—, alkyl-O₂C—, formyl or    unsubstituted or substituted phenyl wherein the substituents are    alkyl or haloalkyl;-   Z is C(O); and-   a is 1.

In still another embodiment of the first aspect of the invention,compounds of formula (I) above are compounds wherein:

-   P and Q is N;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,    C₁-C₆-alkylthio-C₁-C₆-alkyl, C₁-C₆-alkyloxy-C₁-C₆-alkyl, or    C₁-C₆-alkylsulfonyloxy-C₁-C₆-alkyl;-   R₇ is unsubstituted phenyl or phenyl substituted by one or more    substituents selected from the group consisting of C₁-C₆-alkyl,    halo-C₁-C₆-alkyl, phenyl, phenyloxy, C₁-C₆-alkoxy,    halo-C₁-C₆-alkoxy, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio,    halo-C₁-C₆-alkylsulfinyl and halo-C₁-C₆-alkylsulfonyl;-   R₈, R₉, R₁₀ and R₁₁ either, independently of one another, is    hydrogen, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano,    C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₁-C₆-alkylamino,    hydroxy-C₁-C₆-alkyl, formyl, C₁-C₆-alkylamino-C₁-C₆-alkyl, HO₂C—,    C₁-C₆-alkyl-O₂C— or unsubstituted or substituted phenyl wherein the    substituents are C₁-C₆-alkyl or halo-C₁-C₆-alkyl;-   Z is C(O); and-   a is 1.

In still another embodiment of the first aspect of the invention,compounds of formula (I) above are compounds wherein:

-   P and Q is N;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is methyl, ethyl, butyl, CH₂OH, CH₂OCH₃, CH₂SCH₃, CH₂OSO₂CH₃;-   R₇ is a phenyl substituted with butyl, CF₃, phenyl, phenoxy, OCF₃,    SCF₃, SOCF₃, SO₂CF₃;-   R₈, R₉, R₁₀ and R₁₁ either, independently of one another, is    hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂, vinyl, CH₂OH, CH(OH)CH₂OH,    CO₂H, CO₂CH₃, Ph-CF₃, F, Cl, Br, CF₃, OCF₃ or CN;-   Z is C(O); and-   a is 1.

In a second aspect of the invention, compounds of formula (I) above arecompounds wherein:

-   P is N;-   Q is C—R₂;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy,    alkoxyalkoxy, or alkylaminoalkoxy, dialkylaminoalkoxy;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is hydrogen, alkyl, or haloalkyl;-   R₇ is unsubstituted phenyl or phenyl substituted by one or more    substituents selected from the group consisting of alkyl, haloalkyl,    alkoxy, haloalkoxy, alkylthio, haloalkylthio, haloalkylsulfinyl and    haloalkylsulfonyl;-   R₈, R₉, R₁₀ and R₁₁ either together or independently of one another,    are hydrogen, halogen, alkyl, haloalkyl, nitro, amino, amido,    alkyl-O₂C— or alkylcarbonylamino;-   Z is C(O); and-   a is 1.

In another embodiment of the second aspect of the invention, compoundsof formula (I) above are compounds wherein:

-   P is N;-   Q is C—R₂;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,    C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkoxy, or    C₁-C₆-alkylamino-C₁-C₆-alkoxy;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;-   R₇ is unsubstituted phenyl or phenyl substituted by one or more    substituents selected from the group consisting of C₁-C₆-alkyl,    halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, halo-C₁-C₆-alkylsulfinyl and    halo-C₁-C₆-alkylsulfonyl;-   R₈, R₉, R₁₀ and R₁₁ either, independently of one another, is    hydrogen, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, nitro, amino,    amido, C₁-C₆-alkyl-O₂C— or C₁-C₆-alkylcarbonylamino;-   Z is C(O); and-   a is 1.

In still another embodiment of the second aspect of the invention,compounds of formula (I) above are compounds wherein:

-   P is N;-   Q is C—R₂;-   V is C—R₈;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, Cl, methyl, methoxy, ethoxy, propoxy, butoxy,    O(CH₂)₂OCH₃, or O(CH₂)₂N(CH₃)₂;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is methyl;-   R₇ is phenyl substituted by OCF₃, phenoxy, or SCF₃;-   R₈, R₉, R₁₀ and R₁₁ either, independently of one another, is    hydrogen, Cl, Br, C₁-C₆-alkyl, CF₃, nitro, amino, amido, CO₂CH₃, or    NHCOCH₃;-   Z is C(O); and-   a is 1.

In a third aspect of the invention, compounds of formula (I) above arecompounds wherein:

-   P is N;-   Q is C—R₂ or N;-   V is N;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, halogen, alkyl, alkoxy, or haloalkoxy;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is hydrogen, alkyl, or haloalkyl;-   R₇ is unsubstituted phenyl or phenyl substituted by one or more    substituents selected from the group consisting of alkyl, haloalkyl,    alkoxy, haloalkoxy, alkylthio, haloalkylthio, haloalkylsulfinyl and    haloalkylsulfonyl;-   R₉, R₁₀ and R₁₁ either together or independently of one another, are    hydrogen, halogen, alkyl, or haloalkyl;-   Z is C(O); and-   a is 1.

In another embodiment of the third aspect of the invention, compounds offormula (I) above are compounds wherein:

-   P is N;-   Q is C—R₂ or N;-   V is N;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, or    halo-C₁-C₆-alkoxy;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is hydrogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;-   R₇ is unsubstituted phenyl or phenyl substituted by one or more    substituents selected from the group consisting of C₁-C₆-alkyl,    halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylthio,    halo-C₁-C₆-alkylthio, halo-C₁-C₆-alkylsulfinyl and    halo-C₁-C₆-alkylsulfonyl;-   R₉, R₁₀ and R₁₁ either, independently of one another, is hydrogen,    halogen, C₁-C₆-alkyl, or halo-C₁-C₆-alkyl;-   Z is C(O); and-   a is 1.

In still another embodiment of the third aspect of the invention,compounds of formula (I) above are compounds wherein:

-   P is N;-   Q is C—R₂ or N;-   V is N;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, Cl, Br, methoxy;-   R₃, R₄ and R₆ are hydrogen;-   R₅ is methyl;-   R₇ is phenyl substituted by OCF₃ or SCF₃;-   R₉, R₁₀ and R₁₁ either, independently of one another, is hydrogen,    Cl, Br or methyl;-   Z is C(O); and-   a is 1.

In a fourth aspect of the invention, compounds of formula (I) above arecompounds wherein:

-   P is N;-   Q is C—R₂ or N;-   V is C—R₈ or N;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, Cl, Br, methyl or methoxy;-   R₃, R₄ and R₆ is H;-   R₅ is methyl;-   R₇ is phenyl optionally substituted with OCF₃, SCF₃ or CHFCF₃;-   R₈, R₉, R₁₀ and R₁₁, either, independently of one another is H, Cl,    Br, methyl, CF₃ or CN;-   Z is C(O); and-   a is 1.

In another embodiment of the fourth aspect of the invention, compoundsof formula (I) above are compounds wherein:

-   P is N;-   Q is C—R₂ or N;-   V is C—R₈ or N;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, Cl, Br, methyl or methoxy;-   R₃, R₄ and R₆ is H;-   R₅ is methyl;-   R₇ is phenyl substituted with OCF₃, SCF₃ or CHFCF₃;-   R₈ is H, Cl, Br, F or CN;-   R₉ is H, Cl or Br;-   R₁₀ is H, Cl, Br or CF₃;-   R₁₁ is H, Cl, Br or methyl;-   Z is C(O); and-   a is 1.

In a fifth aspect of the invention, compounds of formula (I) above arecompounds wherein:

-   P is N;-   Q is C—R₂ or N;-   V is N;-   W is C—R₉;-   X is C—R₁₀;-   Y is C—R₁₁;-   R₂ is hydrogen, Cl, Br or methoxy;-   R₃, R₄ and R₆ is H;-   R₅ is methyl;-   R₇ is phenyl substituted with OCF₃ or SCF₃;-   R₉ is H;-   R₁₀ is Cl or Br;-   R₁₁ is H;-   Z is C(O); and-   a is 1.    Formulations and Administration for Pharmaceutical/Veterinary Use

Another aspect of the invention is the formation of parasiticidalcompositions which comprise the aryloazol-2-yl-cyanoethylamino compoundsof the invention. The composition of the invention can also be in avariety of forms which include, but are not limited to, oralformulations, injectable formulations, and topical, dermal or subdermalformulations. The formulations are intended to be administered to ananimal which includes but is not limited to mammals, birds and fish.Examples of mammals include but are not limited to humans, cattle,sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats andother livestock or domestic mammals. Examples of birds include turkeys,chickens, ostriches and other livestock or domestic birds.

The composition of the invention may be in a form suitable for oral use,for example, as baits (see, e.g., U.S. Pat. No. 4,564,631), dietarysupplements, troches, lozenges, chewables, tablets, hard or softcapsules, emulsions, aqueous or oily suspensions, aqueous or oilysolutions, oral drench formulations, dispersible powders or granules,premixes, syrups or elixirs, enteric formulations or pastes.Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, bitteringagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc, the tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 (incorporated herein by reference) to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may be hard gelatin capsules, wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin. Capsules may also besoft gelatin capsules, wherein the active ingredient is mixed with wateror miscible solvents such as propylene glycol, PEGs and ethanol, or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase maybe a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monoleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment of the formulation, the composition of the inventionis in the form of a microemulsion. Microemulsions are well suited as theliquid carrier vehicle. Microemulsions are quaternary systems comprisingan aqueous phase, an oily phase, a surfactant and a cosurfactant. Theyare translucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets ofthe aqueous phase in the oily phase or conversely of microdroplets ofthe oily phase in the aqueous phase. The size of these microdroplets isless than 200 nm (1000 to 100,000 nm for emulsions). The interfacialfilm is composed of an alternation of surface-active (SA) andco-surface-active (Co-SA) molecules which, by lowering the interfacialtension, allows the microemulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase can be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase comprises oftriglycerides; in another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. In another embodiment of the oily phasewill represent a % v/v range selected from the group consisting of about2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of themicroemulsion.

The aqueous phase includes, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment of the glycol derivatives, the glycol isselected from the group consisting of propylene glycol, diethyleneglycol monoethyl ether, dipropylene glycol monoethyl ether and mixturesthereof. Generally, the aqueous phase will represent a proportion fromabout 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion include diethylene glycol monoethylether, dipropylene glycol monomethyl ether, polyglycolyzed C₈-C₁₀glycerides or polyglyceryl-6 dioleate. In addition to these surfactants,the cosurfactants include short-chain alcohols, such as ethanol andpropanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and cosurfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same formulation. In one embodiment for the amount ofsurfactant/cosurfactant, the cosurfactant to surfactant ratio will befrom about 1/7 to about 1/2. In another embodiment for the amount ofcosurfactant, there will be from about 25 to about 75% v/v of surfactantand from about 10 to about 55% v/v of cosurfactant in the microemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, atachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and/or coloring agent(s).

In another embodiment of the invention, the composition can be in pasteform. Examples of embodiments in a paste form include but are notlimited to those described in U.S. Pat. Nos. 6,787,342 and 7,001,889(each of which are incorporated herein by reference). In addition to thearyloazol-2-yl cyanoethylamino compound of the invention, the paste canalso contain fumed silica; a viscosity modifier; a carrier; optionally,an absorbent; and optionally, a colorant, stabilizer, surfactant, orpreservative.

The process for preparing a paste formulation comprises the steps of:

(a) dissolving or dispersing the aryloazol-2-yl cyanoethylamino compoundinto the carrier by mixing;

(b) adding the fumed silica to the carrier containing the dissolvedaryloazol-2-yl cyanoethylamino compound and mixing until the silica isdispersed in the carrier;

(c) allowing the intermediate formed in (b) to settle for a timesufficient in order to allow the air entrapped during step (b) toescape; and

(d) adding the viscosity modifier to the intermediate with mixing toproduce a uniform paste.

The above steps are illustrative, but not limiting. For example, step(a) can be the last step. In one embodiment of the formulation, theformulation is a paste containing aryloazol-2-yl cyanoethylaminocompound, fumed silica, a viscosity modifier, an absorbent, a colorant;and a hydrophilic carrier which is triacetin, a monoglyceride, adiglyceride, or a triglyceride.

The paste may also include, but is not limited to, a viscosity modifierselected from the group consisting of PEG 200, PEG 300, PEG 400, PEG600, monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80),and polyoxamers (e.g., Pluronic L 81); an absorbent selected from thegroup consisting of magnesium carbonate, calcium carbonate, starch, andcellulose and its derivatives; and a colorant selected from the groupconsisting of titanium dioxide iron oxide, and FD&C Blue #1 AluminumLake.

The compositions may be in the form of a sterile injectable aqueous oroleagenous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that may be employed are water, Ringers solutionand isotonic sodium chloride solution. Cosolvents such as ethanol,propylene glycol glycerol formal or polyethylene glycols may also beused. Preservatives, such as phenol or benzyl alcohol, may be used.

In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations can include emulsions,creams, ointments, gels, pastes, powders, shampoos, pour-onformulations, ready-to-use formulations, spot-on solutions andsuspensions, dips and sprays. Topical application of an inventivecompound or of a composition including at least one inventive compoundamong active agent(s) therein, a spot-on or pour-on composition, canallow for the inventive compound to be absorbed through the skin toachieve systemic levels, distributed through the sebaceous glands or onthe surface of the skin achieving levels throughout the haircoat. Whenthe compound is distributed through the sebaceous glands, they can actas a reservoir, whereby there can be a long-lasting effect (up toseveral months) effect. Spot-on formulations are typically applied in alocalized region which refers to an area other than the entire animal.In one embodiment of a localized region, the location is between theshoulders. In another embodiment of a localized region it is a stripe,e.g. a stripe from head to tail of the animal.

Pour-on formulations are described in U.S. Pat. No. 6,010,710,incorporated herein by reference. The pour-on formulations may beadvantageously oily, and generally comprise a diluent or vehicle andalso a solvent (e.g. an organic solvent) for the active ingredient ifthe latter is not soluble in the diluent.

Organic solvents that can be used in the invention include but are notlimited to: acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, butyl diglycol, dimethylacetamide, dimethylformamide,dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol,ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,monomethylacetamide, dipropylene glycol monomethyl ether, liquidpolyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g.N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycoland diethyl phthalate, or a mixture of at least two of these solvents.

As vehicle or diluent, mention may be made of plant oils such as, butnot limited to soybean oil, groundnut oil, castor oil, corn oil, cottonoil, olive oil, grape seed oil, sunflower oil, coconut oils etc.;mineral oils such as, but not limited to, petrolatum, paraffin,silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, forexample, medium-chain (such as C8 to C12) triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent can be added. One embodiment of the emollientand/or spreading and/or film-forming agent are those agents selectedfrom the group consisting of:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;lecithin, sodium carboxymethylcellulose, silicone oils,polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils),for example those containing silanol functionalities, or a 45V2 oil,(b) anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulphates (e.g. sodium lauryl sulphate and sodium cetylsulphate); sodium dodecylbenzenesulphonate, sodiumdioctylsulphosuccinate; fatty acids (e.g. those derived from coconutoil),(c) cationic surfactants such as water-soluble quaternary ammonium saltsof formula N⁺R′R″R′″R″″, Y⁻ in which the radicals R are optionallyhydroxylated hydrocarbon radicals and Y⁻ is an anion of a strong acidsuch as the halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is among the cationic surfactants whichcan be used,(d) amine salts of formula N⁺HR′R″R′″ in which the radicals R areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants which can be used,(e) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,(f) amphoteric surfactants such as the substituted lauryl compounds ofbetaine; or(g) a mixture of at least two of these agents.

The solvent will be used in proportion with the concentration of thearyloazol-2-yl cyanoethylamino compound and its solubility in thissolvent. It will be sought to have the lowest possible volume. Thevehicle makes up the difference to 100%.

In one embodiment of the amount of emollient, the emollient is used in aproportion selected from the group consisting of from 0.1 to 50% and0.25 to 5%, by volume.

In another embodiment of the invention, the composition can be inready-to-use solution form as is described in U.S. Pat. No. 6,395,765,incorporated herein by reference. In addition to the aryloazol-2-ylcyanoethylamino compound, the ready-to-use solution can contain acrystallization inhibitor, an organic solvent and an organic co-solvent.

In one embodiment of the amount of crystallization inhibitor, thecrystallization inhibitor can be present in a proportion selected fromthe group consisting of about 1 to about 20% (w/v) and about 5 to about15%. In another embodiment of the amount of crystallization inhibitor,the amount corresponds to the test in which 0.3 ml of a solutioncomprising 10% (w/v) of aryloazol-2-yl cyanoethylamino compound in theliquid carrier and 10% of the inhibitor are deposited on a glass slideat 20° C. and allowed to stand for 24 hours. The slide is then observedwith the naked eye. Acceptable inhibitors are those whose additionprovides for few (e.g. less than ten crystals) or no crystal.

The organic solvent has a dielectric constant of a range selected fromthe group consisting of between about 10 and 35 and between about 20 and30, the content of this organic solvent in the overall compositionrepresenting the complement to 100% of the composition; and the organicco-solvent having a boiling point selected from the ranges consisting ofbelow 100° C., and below 80° C., and having a dielectric constant of arange selected from the group consisting of between about 10 and 40 andbetween about 20 and 30; this co-solvent may be present in thecomposition in a organic co-solvent/organic solvent weight/weight (W/W)ratio of between about 1/15 and 1/2. The solvent is volatile so as toact as a drying promoter, and is miscible with water and/or with theorganic solvent.

The formulation can also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent being present in a proportionselected from a range consisting of about 0.005 to about 1% (w/v) andabout 0.01 to about 0.05%.

Crystallization inhibitors which are useful for the invention includebut are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan;lecithin or sodium carboxymethylcellulose; or acrylic derivatives, suchas methacrylates and others;(b) anionic surfactants, such as alkaline stearates (e.g. sodium,potassium or ammonium stearate); calcium stearate or triethanolaminestearate; sodium abietate; alkyl sulphates, which include but are notlimited to sodium lauryl sulphate and sodium cetyl sulphate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids (e.g. coconut oil);(c) cationic surfactants, such as water-soluble quaternary ammoniumsalts of formula N⁺R′R″R′″R″″Y⁻, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals and Y⁻ is ananion of a strong acid, such as halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used;(d) amine salts of formula N⁺HR′R″R′″, in which the R radicals areidentical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used;(e) non-ionic surfactants, such as optionally polyoxyethylenated estersof sorbitan, e.g. Polysorbate 80, or polyoxyethylenated alkyl ethers;polyethylene glycol stearate, polyoxyethylenated derivatives of castoroil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids or copolymers of ethylene oxide and ofpropylene oxide;(f) amphoteric surfactants, such as substituted lauryl compounds ofbetaine; or(g) a mixture of at least two of the compounds listed in (a)-(f) above.

In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected from the compoundsmentioned above as crystallization inhibitor.

In one embodiment of the film-forming agent, the agents are of thepolymeric type which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants; in anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan and in yet another embodiment ofthe surface-active agent, the agents include the various grades ofpolysorbate, for example Polysorbate 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent can be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned elsewhere.

The pair thus constituted secures, in a noteworthy way, the objectivesof absence of crystallization on the coat and of maintenance of thecosmetic appearance of the skin or fur, that is to say without atendency towards sticking or towards a sticky appearance, despite thehigh concentration of active material.

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include but is not limited to butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate or a mixture of notmore than two of them.

The formulation adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

The volume applied can be of the order of about 0.3 to about 1 ml. Inone embodiment for the volume, the volume is on the order of about 0.5ml, for cats and on the order of about 0.3 to about 3 ml for dogs,depending on the weight of the animal.

In another embodiment of the invention, application of a spot-onformulation according to the present invention can also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

For spot-on formulations, the carrier can be a liquid carrier vehicle asdescribed in U.S. Pat. No. 6,426,333 (incorporated herein by reference),which in one embodiment of the spot-on formulation comprises a solventand a cosolvent wherein the solvent is selected from the groupconsisting of acetone, acetonitrile, benzyl alcohol, butyl diglycol,dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether, monomethylacetamide, dipropyleneglycol monomethyl ether, liquid polyoxyethylene glycols, propyleneglycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycolmonoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters,such as the diethyl ester or diisobutyl adipate, and a mixture of atleast two of these solvents and the cosolvent is selected from the groupconsisting of absolute ethanol, isopropanol or methanol.

The liquid carrier vehicle can optionally contain a crystallizationinhibitor selected from the group consisting of an anionic surfactant, acationic surfactant, a non-ionic surfactant, an amine salt, anamphoteric surfactant or polyvinylpyrrolidone, polyvinyl alcohols,copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols,benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenatedsorbitan esters; lecithin, sodium carboxymethylcellulose, and acrylicderivatives, or a mixture of these crystallization inhibitors.

Spot-on formulations may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on formulation can be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These formulations will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host.

Dosage forms may contain from about 0.5 mg to about 5 g of an activeagent. In one embodiment of the dosage form, the dosage is from about 1mg to about 500 mg of an active agent, typically about 25 mg, about 50mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg, about 800 mg, or about 1000 mg.

In one embodiment of the invention, the active agent is present in theformulation at a concentration of about 0.05 to 10% weight/volume. Inanother embodiment of the invention, the active agent is present in theformulation as a concentration from about 0.1 to 2% weight/volume. Inyet another embodiment of the invention, the active agent is present inthe formulation as a concentration from about 0.25 to about 1.5%weight/volume. In still another embodiment of the invention, the activeagent is present in the formulation as a concentration about 1%weight/volume.

Another embodiment of the invention is directed toward a method oftreating endoparasiticidal infection in a mammal in need thereof whichcomprising administering an effective amount of the compound of theinvention.

In one embodiment for treating endoparasiticidal infection is that thehelminth is selected from the group consisting of but not limited toAnaplocephala (Anoplocephala), Ancylostoma, Anecator, Ascaris, Brugia,Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus,Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus,Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus,Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus,Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum,Onchocerca, Ostertagia, Oxyuris, Paracaris, Schistosoma, Strongylus,Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris,Trichostrongylus, Triodontophorous, Uncinaria, Wuchereria, andcombinations thereof.

In another embodiment of the invention, the helminth is Haemonchuscontortus, Ostertagia circumcincta, Trichostrongylus axei,Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battusand combinations thereof.

Another embodiment of the invention is directed toward a method oftreating ectoparasiticidal infection in a mammal in need thereof whichcomprises administering an effective amount of the compound of theinvention.

In one embodiment for treating ectoparasiticidal infection, the infectedis selected from the group consisting of but not limited to fleas,ticks, mites, mosquitoes, flies, lice, blowfly and combinations thereof.

Formulations and Administration for Agrochemical Use

The compounds of the formula (I) or their salts can be employed as suchor in the form of their preparations (formulations) as combinations withother pesticidally active substances, such as, for example,insecticides, attractants, sterilants, acaricides, nematicides,herbicides, fungicides, and with safeners, fertilizers and/or growthregulators, for example as a premix/readymix.

The insecticides include, for example, phosphoric esters, carbamates,carboxylic esters, chlorinated hydrocarbons, phenylureas, substancesprepared by microorganisms.

Examples of insecticides which may optionally be admixed include but arenot limited to:

phosphoric esters, such as azinphos-ethyl, azinphos-methyl,α-1(4-chlorophenyl)-4-(O-ethyl, S-propyl)phosphoryloxy-pyrazole,chlorpyrifos, coumaphos, demeton, demeton-S-methyl, diazinon,dichlorvos, dimethoate, ethoate, ethoprophos, etrimfos, fenitrothion,fenthion, heptenophas, parathion, parathion-methyl, phosalone, poxim,pirimiphos-ethyl, pirimiphos-methyl, profenofos, prothiofos, sulfprofos,triazophos and trichlorphon;carbamates, such as aldicarb, bendiocarb, α-2-(1-methylpropyl)-phenylmethylcarbamate, butocarboxim, butoxycarboxim, carbaryl, carbofuran,carbosulfan, cloethocarb, isoprocarb, methomyl, oxamyl, pirimicarb,promecarb, propoxur and thiodicarb;organosilicon compounds (e.g. dimethyl(phenyl)silyl-methyl3-phenoxybenzyl ethers, such as dimethyl-(4-ethoxyphenyl)-silylmethyl3-phenoxybenzyl ether) or (dimethylphenyl)-silyl-methyl2-phenoxy-6-pyridylmethyl ethers such as, for example,dimethyl-(9-ethoxy-phenyl)-silylmethyl 2-phenoxy-6-pyridylmethyl etheror [(phenyl)-3-(3-phenoxyphenyl)-propyl[(dimethyl)-silanes such as, forexample,(4-ethoxyphenyl)-[3-(4-fluoro-3-phenoxyphenyl-propyl]dimethyl-silane,silafluofen;pyrethroids (which are also useful for their repellent properties, e.g.against mosquitoes), such as allethrin, alphamethrin, bioresmethrin,byfenthrin, cycloprothrin, cyfluthirin, decamethrin, cyhalothrin,cypermethrin, deltamethrin, alpha-cyano-3-phenyl-2-methylbenzyl2,2-dimethyl-3-(2-chloro-2-trifluoro-methylvinyl)cyclopropane-carboxylate,fenpropathrin, fenfluthrin, fenvalerate, flucythrinate, flumethrin,fluvalinate, permethrin, resmethrin and tralomethrin;nitroimines and nitromethylenes, such as1-[(6-chloro-3-pyridinyl)-methyl]-4,5-dihydro-N-nitro-1H-imidazole-2-amine(imidacloprid),N-[(6-chloro-3-pyridyl)-methyl]-N²-cyano-N¹-methylacetamide (NI-25);abamectin, AC 303, 630 (chlorfenapyr), acephate, acrinathrin, alanycarb,aldoxycarb, aldrin, amitraz, azamethiphos, Bacillus thuringiensis,phosmet, phosphamidon, phosphine, prallethrin, propaphos, propetamphos,prothoate, pyraclofos, pyrethrins, pyridaben, pyridafenthion,pyriproxyfen, quinalphos, RH-7988, rotenone, sodium fluoride, sodiumhexafluorosilicate, sulfotep, sulfuryl fluoride, tar oils,teflubenzuron, tefluthrin, temephos, terbufos, tetrachlorvinphos,tetramethrin, O-2-tert-butyl-pyrimidin-5-yl-o-isopropylphosphorothiate,thiocyclam, thiofanox, thiometon, tralomethrin, triflumuron,trimethacarb, vamidothion, Verticillium Lacanii, XMC, xylylcarb,benfuracarb, bensultap, bifenthrin, bioallethrin, MERbioallethrin(S)-cyclopentenyl isomer, bromophos, bromophos-ethyl, buprofezin,cadusafos, calcium polysulphide, carbophenothion, cartap,quinomethionate, chlordane, chlorfenvinphos, chlorfluazuron,chlormephos, chloropicrin, chlorpyrifos, cyanophos, beta-cyfluthrin,alphacypermethrin, cyophenothrin, cyromazine, dazomet, DDT,demeton-S-methylsulphone, diafenthiuron, dialifos, dicrotophos,diflubenzuron, dinoseb, deoxabenzofos, diazacarb, disulfoton, DNOC,empenthrin, endosulfan, EPN, esfenvalerate, ethiofencarb, ethion,etofenprox, fenobucarb, fenoxycarb, fensulfothion, fipronil,flucycloxuron, flufenprox, flufenoxuron, fonofos, formetanate,formothion, fosmethilan, furathiocarb, heptachlor, hexaflumuron,hydramethylnon, hydrogen cyanide, hydroprene, IPSP, isazofos,isofenphos, isoprothiolane, isoxathion, iodfenphos, kadethrin, lindane,malathion, mecarbam, mephosfolan, mercurous chloride, metam,metarthizium, anisopliae, methacrifos, methamidophos, methidathion,methiocarb, methoprene, methoxychlor, methyl isothiocyanate, metholcarb,mevinphos, monocrotophos, naled, Neodiprion sertifer NPV, nicotine,omethoate, oxydemeton-methyl, pentachlorophenol, petroleum oils,phenothrin, phenthoate, phorate.

Other insecticides that may optionally be admixed may also be from theclass of the compounds described by U.S. Pat. No. 7,001,903.

Fungicides which may optionally be admixed are include but are notlimited to:

(1) Triazoles which include but are not limited to:

azaconazole, propiconazole, tebuconazole, cyproconazole, metconazole,amitrole, azocyclotin, BAS 480F, bitertanol, difenoconazole,fenbuconazole, fenchlorazole, fenethanil, fluquinconazole, flusilazole,flutriafol, imibenconazole, isozofos, myclobutanil, paclobutrazol,(±)-cis-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)-cycloheptanol,tetraconazole, triadimefon, triadimenol, triapenthenol, triflumizole,triticonazole, uniconazole and their metal salts and acid adducts.(2) Imidazoles which include but are not limited to:imazalil, pefurazoate, prochloraz, triflumizole,2-(1-tert-butyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol,thiazolecarboxanilides such as2′,6′-dibromo-2-methyl-4-trifluoromethoxy-4′-trifluoromethyl-1,3-thiazole-5-carboxanilide,1-imidazolyl-1-(4′-chlorophenoxy)-3,3-dimethylbutan-2-one and theirmetal salts and acid adducts.(3) “Methyl (E)-2-phenyl-3-methoxyacrylate” compounds which include butare not limited to:

-   methyl    (E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]3-methoxyacrylate,-   methyl    (E)-2-[2-[6-(2-thioamidophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[6-(2,6-difluorophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[3-(pyrimidin-2-yloxy)phenoxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[3-(5-methylpyrimidin-2-yloxy)-phenoxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[3-(phenyl-sulphonyloxy)phenoxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[3-(4-nitrophenoxy)phenoxy]phenyl]-3-methoxyacrylate,-   methyl (E)-2-[2-phenoxyphenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-(3,5-dimethyl-benzoyl)pyrrol-1-yl]-3-methoxyacrylate,-   methyl (E)-2-[2-(3-methoxyphenoxy)phenyl]-3-methoxyacrylate,-   methyl (E)-2[2-(2-phenylethen-1-yl)-phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-(3,5-dichlorophenoxy)pyridin-3-yl]-3-methoxyacrylate,-   methyl    (E)-2-(2-(3-(1,1,2,2-tetrafluoroethoxy)phenoxy)phenyl)-3-methoxyacrylate,-   methyl    (E)-2-(2-[3-(alpha-hydroxybenzyl)phenoxy]phenyl)-3-methoxyacrylate,-   methyl (E)-2-(2-(4-phenoxypyridin-2-yloxy)phenyl)-3-methoxyacrylate,-   methyl (E)-2-[2-(3-n-propyloxyphenoxy)phenyl]3-methoxyacrylate,-   methyl (E)-2-[2-(3-isopropyloxyphenoxy)phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[3-(2-fluorophenoxy)phenoxy]phenyl]-3-methoxyacrylate,-   methyl (E)-2-[2-(3-ethoxyphenoxy)phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-(4-tert-butyl-pyridin-2-yloxy)phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[3-(3-cyanophenoxy)phenoxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[(3-methylpyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[6-(2-methylphenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-(5-bromo-pyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-(3-(3-iodopyridin-2-yloxy)phenoxy)phenyl]-3-methoxyacrylate,-   methyl    (E)-2-[2-[6-(2-chloropyridin-3-yloxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,    methyl    (E),(E)-2-[2-(5,6-di-methylpyrazin-2-ylmethyloximinomethyl)phenyl]-3-methoxyacrylate,-   methyl    (E)-2-{2-[6-(6-methylpyridin-2-yloxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate,    methyl    (E),(E)-2-{2-(3-methoxyphenyl)methyloximinomethyl]-phenyl}-3-methoxyacrylate,    methyl    (E)-2-{2-(6-(2-azidophenoxy)-pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate,-   methyl    (E),(E)-2-{2-[6-phenylpyrimidin-4-yl)-methyloximinomethyl]phenyl}-3-methoxyacrylate,-   methyl    (E),(E)-2-{2-[(4-chlorophenyl)-methyloximinomethyl]-phenyl}-3-methoxyacrylate,    methyl    (E)-2-{2-[6-(2-n-propylphenoxy)-1,3,5-triazin-4-yloxy]phenyl}-3-methoxyacrylate,    and methyl    (E),(E)-2-{2-[(3-nitrophenyl)methyloximinomethyl]phenyl}-3-methoxyacrylate;    (4) Succinate Dehydrogenase Inhibitors which include but are not    limited to:    -   (a) fenfuram, furcarbanil, cyclafluramid, furmecyclox, seedvax,        metsulfovax, pyrocarbolid, oxycarboxin, shirlan, mebenil        (mepronil), benodanil, flutolanil (Moncut);    -   (b) naphthalene derivatives such as terbinafine, naftifine,        butenafine, 3-chloro-7-(2-aza-2,7,7-trimethyl-oct-3-en-5-ine);    -   (c) sulphenamides such as dichlofluanid, tolylfluanid, folpet,        fluorfolpet; captan, captofol;    -   (d) benzimidazoles such as carbendazim, benomyl, furathiocarb,        fuberidazole, thiophonatmethyl, thiabendazole or their salts;    -   (e) morpholine derivatives such as fenpropimorph, falimorph,        dimethomorph, dodemorph, aldimorph, fenpropidine and their        arylsulphonates, such as, for example, p-toluenesulphonic acid        and p-dodecylphenyl-sulphonic acid;    -   (f) dithiocarbamates, cufraneb, ferbam, mancopper, mancozeb,        maneb, metam, metiram, thiram zeneb, ziram;    -   (g) benzothiazoles, such as 2-mercaptobenzothiazole;    -   (h) benzamides, such as        2,6-dichloro-N-(4-trifluoromethylbenzyl)-benzamide;    -   (i) boron compounds, such as boric acid, boric esters, borax;    -   (j) formaldehyde and formaldehyde-releasing compounds, such as        benzyl alcohol mono-(poly)-hemiformal, oxazolidine,        hexa-hydro-S-triazines, N-methylolchloroacetamide,        paraformaldehyde, nitropyrin, oxolinic acid, tecloftalam;    -   (k) tris-N-(cyclohexyldiazeniumdioxy)-aluminium,        N-(cyclo-hexyldiazeniumdioxy)-tri-butyltin or K salts,        bis-N-(cyclohexyldiazeniumdioxy)-copper,        N-methylisothiazolin-3-one, 5-chloro-N-methylisothiazolin-3-one,        4,5-dichloro-N-octylisothiazolin-3-one,        N-octyl-isothiazolin-3-one, 4,5-trimethylene-isothiazolinone,        4,5-benzoisothiazolinone, N-methylolchloroacetamide;    -   (l) aldehydes, such as cinnamaldehyde, formaldehyde,        glutaraldehyde, β-bromo-cinnamaldehyde;    -   (m) thiocyanates, such as thiocyanatomethylthiobenzothiazole,        methylenebisthiocyanate, and the like;    -   (n) quaternary ammonium compounds, such as        benzyldimethyltetradecylammonium chloride,        benzyldimethyldodecylanmuonium chloride, didecyldimethylammonium        chloride;    -   (o) iodine derivatives, such as diiodomethyl p-tolyl sulphone,        3-iodo-2-propinyl alcohol, 4-chlorophenyl-3-iodopropargyl        formal, 3-bromo-2,3-diiodo-2-propenyl ethylcarbamate,        2,3,3-triiodoallyl alcohol, 3-bromo-2,3-diiodo-2-propenyl        alcohol, 3-iodo-2-propinyl n-butylcarbamate, 3-iodo-2-propinyl        n-hexylcarbamate, 3-iodo-2-propinyl cyclohexyl-carbamate,        3-iodo-2-propinyl phenylcarbamate;    -   (p) phenol derivatives, such as tribromophenol,        tetrachlorophenol, 3-methyl-4-chlorophenol,        3,5-dimethyl-4-chlorophenol, phenoxyethanol, dichlorophene,        o-phenylphenol, m-phenylphenol, p-phenylphenol,        2-benzyl-4-chlorophenol and their alkali metal and alkaline        earth metal salts;    -   (q) microbicides having an activated halogen group, such as        chloroacetamide, bronopol, bronidox, tectamer, such as        2-bromo-2-nitro-1,3-propanediol, 2-bromo-4′-hydroxyacetophenone,        2,2-dibromo-3-nitrile-propionamide,        1,2-dibromo-2,4-dicyanobutane, β-bromo-β-nitrostyrene;    -   (r) pyridines, such as 1-hydroxy-2-pyridinethione (and their Na,        Fe, Mn, Zn salts), tetrachloro-4-methylsulphonylpyridine,        pyrimethanol, mepanipyrim, dipyrithion,        1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridine;    -   (s) metal soaps, such as tin naphthenate, copper naphthenate,        zinc naphthenate, tin octoate, copper octoate, zinc octoate, tin        2-ethylhexanoate, copper 2-ethylhexanoate, zinc        2-ethylhexanoate, tin oleate, copper oleate, zinc oleate, tin        phosphate, copper phosphate, zinc phosphate, tin benzoate,        copper benzoate and zinc benzoate;    -   (t) metal salts, such as copper hydroxycarbonate, sodium        dichromate, potassium dichromate, potassium chromate, copper        sulphate, copper chloride, copper borate, zinc fluorosilicate,        copper fluorosilicate, and mixtures with fixatives;    -   (u) oxides, such as tributyltin oxide, Cu₂O, CuO, ZnO;    -   (v) dialkyldithiocarbamates, such as Na and Zn salts of        dialkyldithiocarbamates, tetramethylthiuram disulphide,        potassium N-methyl-dithiocarbamate;    -   (w) nitriles, such as 2,4,5,6-tetrachloroisophthalodinitrile,        disodium cyano-dithioimido-carbamate;    -   (x) quinolines, such as 8-hydroxyquinoline, and their Cu salts;    -   (y) mucochloric acid, 5-hydroxy-2(5H)-furanone;    -   (z) 4,5-dichlorodithiazolinone, 4,5-benzodithiazolinone,        4,5-trimethylenedithiazolinone,        4,5-dichloro-(3H)-1,2-dithiol-3-one,        3,5-dimethyl-tetrahydro-1,3,5-thiadiazine-2-thione,        N-(2-p-chlorobenzoylethyl)-hexaminium chloride, potassium        N-hydroxymethyl-N′-methyl-dithiocarbamate,        2-oxo-2-(4-hydroxy-phenyl)acetohydroximic acid chloride,        phenyl-(2-chloro-cyano-vinyl)sulphone,        phenyl-(1,2-dichloro-2-cyano-vinyl)sulphone; and    -   (aa) Ag-, Zn- or Cu-containing zeolites, alone or enclosed in        polymeric active compounds, or    -   (bb) mixtures of more than one of the abovementioned fungicides.        Herbicides which are known from the literature and which can be        mentioned, which can be combined with the compounds of the        formula (I), are, for example, the following active substances        (Note: the compounds are either designated by the common name        according to the International Organization for Standardization        (ISO) or using the chemical name, if appropriate together with a        customary code number):        acetochlor; acifluorfen(-sodium); aclonifen; AKH 7088, i.e.        [[[1-[5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrophenyl]-2-methoxyethylidene]amino]oxy]acetic        acid and its methyl ester; alachlor; alloxydim(-sodium);        ametryn; amicarbazone, amidochlor, amidosulfuron; amitrol; AMS,        i.e. ammonium sulfamate; anilofos; asulam; atrazine; azafenidin;        azimsulfuron (DPX-A8947); aziprotryn; barban; BAS 516H, i.e.        5-fluoro-2-phenyl-4H-3,1-benzoxazin-4-one; beflubutamid;        benazolin(-ethyl); benfluralin; benfuresate;        bensulfuron(-methyl); bensulide; bentazone(-sodium);        benzobicyclone; benzofenap; benzofluor; benzoylprop(-ethyl);        benzthiazuron; bialaphos (bilanafos); bifenox;        bispyribac(-sodium); bromacil; bromobutide; bromofenoxim;        bromoxynil; bromuron; buminafos; busoxinone; butachlor;        butafenacil; butamifos; butenachlor; buthidazole; butralin;        butroxydim; butylate; cafenstrole (CH-900); carbetamide;        carfentrazone(-ethyl); caloxydim, CDAA, i.e.        2-chloro-N,N-di-2-propenylacetamide; CDEC, i.e.        2-chloroallyldiethyldithiocarbamate; chlomethoxyfen; chloramben;        chlorazifop-butyl; chlorbromuron; chlorbufam; chlorfenac;        chlorflurenol-methyl; chloridazon; chlorimuron(-ethyl);        chlornitrofen; chlorotoluron; chloroxuron; chlorpropham;        chlorsulfuron; chlorthal-dimethyl; chlorthiamid; chlortoluron,        cinidon(-methyl or -ethyl), cinmethylin; cinosulfuron;        clethodim; clefoxydim, clodinafop and its ester derivatives (for        example clodinafop-propargyl); clomazone; clomeprop;        cloproxydim; clopyralid; clopyrasulfuron(-methyl);        cloransulam(-methyl); cumyluron (JC 940); cyanazine; cycloate;        cyclosulfamuron (AC 104); cycloxydim; cycluron; cyhalofop and        its ester derivatives (for example butyl-ester, DEH-112);        cyperquat; cyprazine; cyprazole; daimuron; 2,4-D; 2,4-DB;        dalapon; dazomet, desmedipham; desmetryn; di-allate; dicamba;        dichlobenil; dichlorprop(-P); diclofop and its esters such as        diclofop-methyl; diclosulam, diethatyl(-ethyl); difenoxuron;        difenzoquat; diflufenican; diflufenzopyr; dimefuron;        dimepiperate; dimethachlor; dimethametryn; dimethenamid        (SAN-582H); dimethenamid(-P); dimethazone, dimethipin;        dimexyflam, dimetrasulfuron, dinitramine; dinoseb; dinoterb;        diphenamid; dipropetryn; diquat; dithiopyr; diuron; DNOC;        eglinazine-ethyl; EL 77, i.e.        5-cyano-1-(1,1-dimethylethyl)-N-methyl-1H-pyrazole-4-carboxamide;        endothal; epoprodan, EPTC; esprocarb; ethalfluralin;        ethametsulfuron-methyl; ethidimuron; ethiozin; ethofumesate;        ethoxyfen and its esters (for example ethyl ester, HC-252),        ethoxysulfuron, etobenzanid (HW 52); F5231, i.e.        N-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-phenyl]ethanesulfonamide;        fenoprop; fenoxan, fenoxapropand fenoxaprop-P and their esters,        for example fenoxaprop-P-ethyl and fenoxaprop-ethyl; fenoxydim;        fentrazamide; fenuron; flamprop(-methyl or -isopropyl or        -isopropyl-L); flazasulfuron; florasulam; fluazifop and        fluazifop-P and their esters, for example fluazifop-butyl and        fluazifop-P-butyl; fluazolate, flucarbazone(-sodium);        fluchloralin; flufenacet (FOE 5043), flufenpyr, flumetsulam;        flumeturon; flumiclorac(-pentyl); flumioxazin (S-482);        flumipropyn; fluometuron; fluorochloridone, fluorodifen;        fluoroglycofen(-ethyl); flupoxam (KNW-739); flupropacil        (UBIC-4243); fluproanate, flupyrsulfuron(-methyl, or -sodium);        flurenol(-butyl); fluridone; fluorochloridone;        fluoroxypyr(-meptyl); flurprimidol, flurtamone;        fluthiacet(-methyl); fluthiamide (also known as flufenacet);        fomesafen; foramsulfuron; fosamine; furilazole (MON 13900),        furyloxyfen; glufosinate(-ammonium);        glyphosate(-isopropylammonium); halosafen; halosulfuron(-methyl)        and its esters (for example the methyl ester, NC-319); haloxyfop        and its esters; haloxyfop-P (=R-haloxyfop) and its esters;        HC-252 (diphenylether), hexazinone; imazamethabenz(-methyl);        imazamethapyr; imazamox; imazapic, imazapyr; imazaquin and salts        such as the ammonium salts; imazethamethapyr; imazethapyr,        imazosulfuron; indanofan; iodosulfuron-(methyl)-(sodium),        ioxynil; isocarbamid; isopropalin; isoproturon; isouron;        isoxaben; isoxachlortole; isoxaflutole; isoxapyrifop;        karbutilate; lactofen; lenacil; linuron; MCPA; MCPB; mecoprop;        mefenacet; mefluidid; mesosulfuron(-methyl); mesotrione; metam,        metamifop, metamitron; metazachlor; methabenzthiazuron;        methazole; methoxyphenone; methyldymron; metobenzuron,        metobromuron; (S-)metolachlor; metosulam (XRD 511); metoxuron;        metribuzin; metsulfuron-methyl; MK-616; molinate; monalide;        monocarbamide dihydrogensulfate; monolinuron; monuron; MT 128,        i.e.        6-chloro-N-(3-chloro-2-propenyl)-5-methyl-N-phenyl-3-pyridazinamine;        MT 5950, i.e.        N-[3-chloro-4-(1-methylethyl)-phenyl]-2-methylpentanamide;        naproanilide; napropamide; naptalam; NC 310, i.e.        4-(2,4-dichlorobenzoyl)-1-methyl-5-benzyloxypyrazole; neburon;        nicosulfuron; nipyraclophen; nitralin; nitrofen; nitrofluorfen;        norflurazon; orbencarb; oryzalin; oxadiargyl (RP-020630);        oxadiazone; oxasulfuron; oxaziclomefone; oxyfluorfen; paraquat;        pebulate; pelargonic acid; pendimethalin; penoxulam;        pentanochlor, pentoxazone; perfluidone; pethoxamid, phenisopham;        phenmedipham; picloram; picolinafen; piperophos; piributicarb;        pirifenop-butyl; pretilachlor; primisulfuron(-methyl);        procarbazone(-sodium); procyazine; prodiamine; profluazole,        profluralin; proglinazine(-ethyl); prometon; prometryn;        propachlor; propanil; propaquizafop; propazine; propham;        propisochlor; propoxycarbazone(-sodium), propyzamide;        prosulfalin; prosulfocarb; prosulfuron (CGA-152005); prynachlor;        pyraclonil, pyraflufen(-ethyl); pyrazolinate; pyrazon;        pyrazosulfuron(-ethyl); pyrazoxyfen; pyribenzoxim; pyributicarb;        pyridafol; pyridate; pyriftalid, pyrimidobac(-methyl);        pyrithiobac(-sodium) (KIH-2031); pyroxofop and its esters (for        example propargyl ester); quinclorac; quinmerac; quinoclamine,        quinofop and its ester derivatives, quizalofop and quizalofop-P        and their ester derivatives, for example quizalofop-ethyl;        quizalofop-P-tefuryl and -ethyl; renriduron; rimsulfuron (DPX-E        9636); S 275, i.e.        2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4,5,6,7-tetrahydro-2H-indazole;        secbumeton; sethoxydim; siduron; simazine; simetryn; SN 106279,        i.e.        2-[[7-[2-chloro-4-(trifluoromethyl)phenoxy]-2-naphthalenyl]oxy]propanoic        acid and its methyl ester; sulcotrione; sulfentrazone        (FMC-97285, F-6285); sulfazuron; sulfometuron(-methyl);        sulfosate (ICI-A0224); sulfosulfuron; TCA; tebutam (GCP-5544);        tebuthiuron; tepraloxydim; terbacil; terbucarb; terbuchlor;        terbumeton; terbuthylazine; terbutryn; TFH 450, i.e.        N,N-diethyl-3-[(2-ethyl-6-methylphenyl)sulfonyl]-1H-1,2,4-triazole-1-carboxamide;        thenylchlor (NSK-850); thiafluamide; thiazafluoron; thiazopyr        (Mon-13200); thidiazimin (SN-24085); thifensulfuron(-methyl);        thiobencarb; tiocarbazil; tralkoxydim; tri-allate; triasulfuron;        triaziflam; triazofenamide; tribenuron(-methyl);        2,3,6-trichlorobenzoic acid (2,3,6-TBA), triclopyr; tridiphane;        trietazine; trifloxysulfuron(-sodium), trifluralin;        triflusulfuron and esters (e.g. methyl ester, DPX-66037);        trimeturon; tritosulfuron; tsitodef; vernolate; WL 110547, i.e.        5-phenoxy-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole; UBH-509;        D-489; LS 82-556; KPP-300; NC-324; NC-330; KH-218; DPX-N8189;        SC-0774; DOWCO-535; DK-8910; V-53482; PP-600; MBH-001; KIH-9201;        ET-751; KIH-6127; KIH-2023 and KIH5996.

Appropriate herbicide safeners include but are not limited to benoxacor,cloquintocet, cyometrinil, cyprosulfamide, dichlormid, dicyclonon,dietholate, fenchlorazole, fenclorim, flurazole, fluxofenim, furilazole,isoxadifen, mefenpyr, mephenate, naphthalic anyhydride and oxabetrinil.

Components which may be employed for the active substances according tothe invention in mixed formulations, for example, known active compoundswhich are based on an inhibition of, for example, acetolactate synthase,acetyl-coenzyme A carboxylase, PS I, PS II, HPPDO, phytoene desaturase,protoporphyrinogen oxidase, glutamine synthetase, cellulosebiosynthesis, 5-enolpyruvylshikimate-3-phosphate synthetase. Suchcompounds, and also other compounds which can be employed, whosemechanism of action is to a degree unknown or different, are described,for example, in Weed Research 26, 441-445 (1986), or “The PesticideManual”, 12th Edition 2000 (hereinbelow also abbreviated to “PM”), TheBritish Crop Protection Council and the Royal Soc. of Chemistry(editors) and literature cited therein.

The compounds of formula (I) can be formulated in various ways,depending on the prevailing biological and/or chemico-physicalparameters. Examples of possible formulations which are suitable are:wettable powders (WP), water-soluble powders (SP), water-solubleconcentrates, emulsifiable concentrates (EC), emulsions (EW) such asoil-in-water and water-in-oil emulsions, sprayable solutions, suspensionconcentrates (SC), dispersions on an oil or water basis, solutions whichare miscible with oil, capsule suspensions (CS), dusts (DP),seed-dressing products, granules for broadcasting and soil application,granules (GR) in the form of microgranules, spray granules, coatedgranules and adsorption granules, water-dispersible granules (WG),water-soluble granules (SG), ULV formulations, microcapsules and waxes.

Solid state forms of the compounds of formula (I) can be prepared bymethods known in the art, e.g. Byrn et al., “Solid-State Chemistry ofDrugs”, 2^(nd) Edition, SSCI Inc., (1999); Glusker et al., “CrystalStructure Analysis—A Primer”, 2^(nd) Edition, Oxford University Press,(1985).

The formulations mentioned can be prepared in a manner known per se, forexample by mixing the active compounds with at least one solvent ordiluent, emulsifier, dispersant and/or binder or fixative, waterrepellent and optionally one or more of a desiccant, UV stabilizer, acolorant, a pigment and other processing auxiliaries.

These individual formulation types are known in principle and described,for example, in: Winnacker-Küchler, “Chemische Technologie” [ChemicalTechnology], Volume 7, C. Hauser Verlag, Munich, 4th Edition 1986; Wadevan Valkenburg, “Pesticide Formulations”, Marcel Dekker, N.Y., 1973; K.Martens, “Spray Drying Handbook”, 3rd Ed. 1979, G. Goodwin Ltd. London.

The necessary formulation auxiliaries such as inert materials,surfactants, solvents and other additives are also known and described,for example, in: Watkins, “Handbook of Insecticide Dust Diluents andCarriers”, 2nd Ed., Darland Books, Caldwell N.J.; H. v. Olphen,“Introduction to Clay Colloid Chemistry”, 2nd Ed., J. Wiley & Sons,N.Y.; C. Marsden, “Solvents Guide”, 2nd Ed., Interscience, N.Y. 1963;McCutcheon's “Detergents and Emulsifiers Annual”, MC Publ. Corp.,Ridgewood N.J.; Sisley and Wood, “Encyclopedia of Surface ActiveAgents”, Chem. Publ. Co. Inc., N.Y. 1964; Schönfeldt,“Grenzflächenaktive Äthylenoxidaddukte” [Surface-active ethylene oxideadducts], Wiss. Verlagsgesell., Stuttgart 1976; Winnacker-Küchler,“Chemische Technologie” [Chemical Technology], Volume 7, C. HauserVerlag, Munich, 4th Ed. 1986.

Wettable powders are preparations which are uniformly dispersible inwater and which, besides the compounds of formula (I), also compriseionic and/or nonionic surfactants (wetters, dispersants), for example,polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols,polyoxyethylated fatty amines, fatty alcohol polyglycol ether sulfates,alkanesulfonates or alkylbenzenesulfonates, sodium lignosulfonate,sodium 2,2′-dinaphthylmethane-6,6′-disulfonate, sodiumdibutylnaphthalenesulfonate or else sodium oleoylmethyltaurinate, inaddition to a diluent or inert substance. To prepare the wettablepowders, the compounds of formula (I) are, for example, ground finely inconventional apparatuses such as hammer mills, blower mills and air-jetmills and mixed with the formulation auxiliaries, either concomitantlyor thereafter.

Emulsifiable concentrates are prepared, for example, by dissolving thecompounds of formula (I) in an organic solvent, for example butanol,cyclohexanone, dimethylformamide, xylene or else higher-boilingaromatics or hydrocarbons or mixtures of these, with addition of one ormore ionic and/or nonionic surfactants (emulsifiers). Emulsifiers whichcan be used are, for example: calcium salts of alkylarylsulfonic acids,such as calcium dodecylbenzenesulfonate or nonionic emulsifiers, such asfatty acid polyglycol esters, alkylaryl polyglycol ethers, fatty alcoholpolyglycol ethers, propylene oxide/ethylene oxide condensates, alkylpolyethers, sorbitan esters such as sorbitan fatty acid esters orpolyoxyethylene sorbitan esters such as polyoxyethylene sorbitan fattyacid esters.

Dusts are obtained by grinding the active substance with finely dividedsolid substances, for example talc or natural clays, such as kaolin,bentonite or pyrophyllite, or diatomaceous earth.

Suspension concentrates may be water- or oil-based. They can beprepared, for example, by wet grinding by means of commerciallyavailable bead mills, if appropriate with addition of surfactants, asthey have already been mentioned above for example in the case of theother formulation types.

Emulsions, for example oil-in-water emulsions (EW), can be prepared forexample by means of stirrers, colloid mills and/or static mixtures usingaqueous organic solvents and, if appropriate, surfactants as they havealready been mentioned above for example in the case of the otherformulation types.

Granules can be prepared either by spraying the compounds of formula (I)onto adsorptive, granulated inert material or by applying activesubstance concentrates onto the surface of carriers such as sand,kaolinites or of granulated inert material, by means of binders, forexample polyvinyl alcohol, sodium polyacrylate or alternatively mineraloils. Suitable active substances can also be granulated in the mannerwhich is conventional for the production of fertilizer granules, ifdesired in a mixture with fertilizers.

Water-dispersible granules are prepared, as a rule, by the customaryprocesses such as spray-drying, fluidized-bed granulation, diskgranulation, mixing in high-speed mixers and extrusion without solidinert material. To prepare disk, fluidized-bed, extruder and spraygranules, see, for example, processes in “Spray-Drying Handbook” 3rd ed.1979, G. Goodwin Ltd., London; J. E. Browning, “Agglomeration”, Chemicaland Engineering 1967, pages 147 et seq.; “Perry's Chemical EngineersHandbook”, 5th Ed., McGraw-Hill, New York 1973, p. 8-57.

In general, the agrochemical preparations comprise a range selected fromthe group consisting of about 0.1 to about 99% by weight and about 0.1to about 95% by weight, of compounds of formula (I).

The concentration of compounds of formula (I) in wettable powders is,for example, about 10 to about 90% by weight, the remainder to 100% byweight being composed of customary formulation components. In the caseof emulsifiable concentrates, the concentration of compounds of formula(I) can amount to ranges selected from the group consisting of about 1%to about 90% and about 5% to about 80% by weight. Formulations in theform of dusts usually comprise in the range selected from the groupconsisting of about 1% to about 30% by weight of compounds of formula(I) and about 5% to about 20% by weight of compounds of formula (I). Forsprayable solutions comprise a range selected from the group consistingof about 0.05% to about 80% by weight of compounds of formula (I) andabout 2% to about 50% by weight of compounds of formula (I). In the caseof water-dispersible granules, the content of compounds of formula (I)depends partly on whether the compounds of formula (I) are in liquid orsolid form and on which granulation auxiliaries, fillers and the likeare being used. The water-dispersible granules, for example, comprise arange selected from the group consisting of between about 1 and about95% and between about 10% and about 80% by weight.

In addition, the formulations of compounds of formula (I) mentionedcomprise, if appropriate, the adhesives, wetters, dispersants,emulsifiers, penetrants, preservatives, antifreeze agents, solvents,fillers, carriers, colorants, antifoams, evaporation inhibitors, pHregulators and viscosity regulators which are conventional in each case.

The mixtures according to the invention can be applied via the soileither pre-emergently or post-emergently. The mixtures according to theinvention can also be applied via the leaf. The mixtures according tothe invention can be employed for seed dressing. It is also possible toapply the mixtures according to the invention via an irrigation system,for example via the water for irrigation.

Other Active Agents for Pharmaceutical/Veterinary Use

Additional pharmaceutical, pesticidal or veterinarily activeingredients, which include, but are not limited to, parasiticidalsincluding acaricides, anthelmintics, endectocides and insecticides, mayalso be added to the compositions of the invention. Anti-parasiticagents can include both ectoparasiticisal and endoparasiticidal agents.Veterinary pharmaceutical agents are well-known in the art (see e.g.Plumb' Veterinary Drug Handbook, 5^(th) Edition, ed. Donald C. Plumb,Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9^(th)Edition, (January 2005)) and include but are not limited to acarbose,acepromazine maleate, acetaminophen, acetazolamide, acetazolamidesodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin,acyclovir, albendazole, albuterol sulfate, alfentanil HCl, allopurinol,alprazolam, altrenogest, amantadine HCl, amikacin sulfate, aminocaproicacid, aminopentamide hydrogen sulfate, aminophylline/theophylline,amiodarone HCl, amitraz, amitriptyline HCl, amlodipine besylate,ammonium chloride, ammonium molybdenate, amoxicillin, amoxicillin,clavulanate potassium, amphotericin B desoxycholate, amphotericin Blipid-based, ampicillin, amprolium HCl, antacids (oral), antivenin,apomorphione HCl, apramycin sulfate, ascorbic acid, asparaginase,aspiring, atenolol, atipamezole HCl, atracurium besylate, atropinesulfate, aurnofin, aurothioglucose, azaperone, azathioprine,azithromycin, baclofen, barbituates, benazepril HCl, betamethasone,bethanechol chloride, bisacodyl, bismuth subsalicylate, bleomycinsulfate, boldenone undecylenate, bromides, bromocriptine mesylate,budenoside, buprenorphine HCl, buspirone HCl, busulfan, butorphanoltartrate, cabergoline, calcitonin salmon, calcitrol, calcium salts,captopril, carbenicillin indanyl sodium, carbimazole, carboplatin,carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium,cefixime, cefoperazone sodium, cefotaxime sodium, cefotetan disodium,cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium,ceftiofur HCl, ceftiaxone sodium, cephalexin, cephalosporins,cephapirin, charcoal (activated), chlorambucil, chloramphenicol,chlordiazepoxide, chlordiazepoxide+/−clidinium bromide, chlorothiazide,chlorpheniramine maleate, chlorpromazine HCl, chlorpropamide,chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine,ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin,clemastine fumarate, clenbuterol HCl, clindamycin, clofazimine,clomipramine HCl, claonazepam, clonidine, cloprostenol sodium,clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate,colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide,cyclosporine, cyproheptadine HCl, cytarabine, dacarbazine,dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolenesodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib,deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate,detomidine HCl, dexamethasone, dexpanthenol, dexraazoxane, dextran,diazepam, diazoxide (oral), dichlorphenamide, dichlorvos, diclofenacsodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol(DES), difloxacin HCl, digoxin, dihydrotachysterol (DHT), diltiazem HCl,dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprosttromethamine, diphenylhydramine HCl, disopyramide phosphate, dobutamineHCl, docusate/DSS, dolasetron mesylate, domperidone, dopamine HCl,doramectin, doxapram HCl, doxepin HCl, doxorubicin HCl, doxycycline,edetate calcium disodium.calcium EDTA, edrophonium chloride,enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrinesulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel,erythromycin, esmolol HCl, estradiol cypionate, ethacrynicacid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac,etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids(essential/omega), felbamate, fenbendazole, fentanyl, ferrous sulfate,filgrastim, finasteride, fipronil, florfenicol, fluconazole,flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixinmeglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate,fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide,gabapentin, gemcitabine HCL, gentamicin sulfate, glimepiride, glipizide,glucagon, glucocorticoid agents, glucosamine/chondroitin sulfate,glutamine, glyburide, glycerine (oral), glycopyrrolate, gonadorelin,grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200(Oxyglobin®), heparin, hetastarch, hyaluronate sodium, hydrazaline HCl,hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone,hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid,imidocarb dipropinate, impenem-cilastatin sodium, imipramine, inaminonelactate, insulin, interferon alfa-2a (human recombinant), iodide(sodium/potassium), ipecac (syrup), ipodate sodium, iron dextran,isoflurane, isoproterenol HCl, isotretinoin, isoxsuprine HCl,itraconazole, ivermectin, kaolin/pectin, ketamine HCl, ketoconazole,ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole,levetiracetam, levothyroxine sodium, lidocaine HCl, lincomycin HCl,liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine,magnesium, mannitol, marbofloxacin, mechlorethamine HCl, meclizine HCl,meclofenamic acid, medetomidine HCl, medium chain triglycerides,medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin,meloxican, melphalan, meperidine HCl, mercaptopurine, meropenem,metformin HCl, methadone HCl, methazolamide, methenaminemandelate/hippurate, methimazole, methionine, methocarbamol,methohexital sodium, methotrexate, methoxyflurane, methylene blue,methylphenidate, methylprednisolone, metoclopramide HCl, metoprolol,metronidaxole, mexiletine HCl, mibolerlone, midazolam HCl milbemycinoxime, mineral oil, minocycline HCl, misoprostol, mitotane, mitoxantroneHCl, morantel tartrate, morphine sulfate, moxidectin, naloxone HCl,mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics,neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram,nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine,novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium,omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillinsodium, oxazepam, oxfendazole, oxibutynin chloride, oxymorphone HCl,oxytretracycline, oxytocin, pamidronate disodium, pancreplipase,pancuronium bromide, paromomycin sulfate, parozetine HCl, pencillamine,general information penicillins, penicillin G, penicillin V potassium,pentazocine, pentobarbital sodium, pentosan polysulfate sodium,pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine HCl,pheylbutazone, phenylephrine HCL, phenypropanolamine HCl, phenyloinsodium, pheromones, parenteral phosphate, phytonadione/vitamin K-1,pimobendan, piperazine, pirlimycin HCL, piroxicam, polysulfatedglycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride,praziquantel, prazosin HCl, prednisolone/prednisone, primidone,procainamide HCl, procarbazine HCl, prochlorperazine, propanthelinebromide, propionibacterium acnes injection, propofol, propranolol HCl,protamine sulfate, pseudoephedrine HCl, psyllium hydrophilic mucilloid,pyrantel pamoate, pyridostigmine bromide, pyrilamine maleate,pyrimethamine, quinacrine HCl, quinidine, ranitidine HCl, rifampin,s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin,selegiline HCL/I-deprenyl, sertraline HCl, sevelamer HCl, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate,somatotropin, sotalol HCl, spectinomycin HCl, spironolactone,stanozolol, streptokinase, streptozocin, succimer, succinylcholinechloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline HCl, terbutaline sulfate, testosterone,tetracycline HCl, thiabendazole, thiacetarsamide sodium, thiamine HCl,thioguanine, thiopental sodium, thiotepa, thyrotropin, tiamulin,ticarcilin disodium, tiletamine HCl/zolazepam HCl, tilmocsin, tiopronin,tobramycin sulfate, tocamide HCl, tolazoline HCl, telfenamic acid,topiramate, tramadol HCl, trimcinolone acetonide, trientine HCl,trilostane, trimepraxine tartrate w/prednisolone, tripelennamine HCl,tylosin, urdosiol, valproic acid, vanadium, vancomycin HCl, vasopressin,vecuronium bromide, verapamil HCl, vinblastine sulfate, vincristinesulfate, vitamin E/selenium, warfarin sodium, xylazine HCl, yohimbineHCl, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate,zonisamide and mixtures thereof.

In one embodiment of the invention, other arylpyrazole compounds such asphenylpyrazoles, as described above in the Background (e.g. fipronil,pyriprole), are known in the art and are suitable for combination withthe aryloazol-2-yl cyanoethylamino compounds of the invention. Examplesof such arylpyrazole compounds include but are not limited to thosedescribed in U.S. Pat. Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329;6,174,540; 6,685,954 and 6,998,131—each assigned to Merial, Ltd.,Duluth, Ga.).

In another embodiment of the invention, nodulisporic acid and itsderivatives (a class of known acaricidal, anthelminitic, anti-parasiticand insecticidal agents) can be added to the compositions of theinvention. These compounds are used to treat or prevent infections inhumans and animals and are described, for example, in U.S. Pat. Nos.5,399,582, 5,962,499, 6,221,894 and 6,399,786. The composition caninclude one or more of the known nodulisporic acid derivatives in theart, including all stereoisomers, such as those described in theliterature cited above.

In another embodiment of the invention, one or more macrocycliclactones, which act as an acaricide, anthelmintic agent and insecticide,can be added to the compositions of the invention.

The macrocyclic lactones also include, but are not limited to,avermectins, such as abamectin, dimadectin, doramectin, emamectin,eprinomectin, ivermectin, latidectin, lepimectin, selamectin andmilbemycins, such as milbemectin, milbemycin D, moxidectin andnemadectin. Also included are the 5-oxo and 5-oxime derivatives of saidavermectins and milbemycins. Examples of combinations of arylpyrazolecompounds with macrocyclic lactones include but are not limited to thosedescribed in U.S. Pat. Nos. 6,426,333; 6,482,425; 6,962,713 and6,998,131—each assigned to Merial, Ltd., Duluth, Ga.

The macrocyclic lactone compounds are known in the art and can beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., “Macrocyclic Lactones in Antiparasitic Therapy”, 2002, by JVercruysse and RS Rew published by CABI Publishing or Albers-Schönberget al. (1981), “Avermectins Structure Determination”, J. Am. Chem. Soc.,103, 4216-4221. For doramectin, “Veterinary Parasitology”, vol. 49, No.1, July 1993, 5-15 may be consulted. For milbemycins, reference may bemade, inter alia, to Davies H. G. et al., 1986, “Avermectins andMilbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983,Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24,5333-5336, U.S. Pat. No. 4,134,973 and EP 0 677 054.

Macrocyclic lactones are either natural products or are semi-syntheticderivatives thereof. The structure of the avermectins and milbemycinsare closely related, e.g., by sharing a complex 16-membered macrocycliclactone ring; milbemycins lack the glycosidic moiety of the avermectins.The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519to Albers-Schönberg et al., and the 22,23-dihydro avermectin compoundsare disclosed in Chabala et al., U.S. Pat. No. 4,199,569. Mention isalso made of Kitano, U.S. Pat. No. 4,468,390, Beuvry et al., U.S. Pat.No. 5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390 336, EP0 002 916, and Ancare New Zealand Patent No. 237 086, inter alia.Naturally occurring milbemycins are described in Aoki et al., U.S. Pat.No. 3,950,360 as well as in the various references cited in “The MerckIndex” 12^(th) ed., S. Budavari, Ed., Merck & Co., Inc. WhitehouseStation, N.J. (1996). Latidectin is described in the “InternationalNonproprietary Names for Pharmaceutical Substances (INN)”, WHO DrugInformation, vol. 17, no. 4, pp. 263-286, (2003). Semisyntheticderivatives of these classes of compounds are well known in the art andare described, for example, in U.S. Pat. No. 5,077,308, U.S. Pat. No.4,859,657, U.S. Pat. No. 4,963,582, U.S. Pat. No. 4,855,317, U.S. Pat.No. 4,871,719, U.S. Pat. No. 4,874,749, U.S. Pat. No. 4,427,663, U.S.Pat. No. 4,310,519, U.S. Pat. No. 4,199,569, U.S. Pat. No. 5,055,596,U.S. Pat. No. 4,973,711, U.S. Pat. No. 4,978,677, U.S. Pat. No.4,920,148 and EP 0 667 054.

In another embodiment of the invention, the class of acaricides orinsecticides known as insect growth regulators (IGRs) can also be addedto the compositions of the invention. Compounds belonging to this groupare well known to the practitioner and represent a wide range ofdifferent chemical classes. These compounds all act by interfering withthe development or growth of the insect pests. Insect growth regulatorsare described, for example, in U.S. Pat. No. 3,748,356; U.S. Pat. No.3,818,047; U.S. Pat. No. 4,225,598; U.S. Pat. No. 4,798,837; U.S. Pat.No. 4,751,225, EP 0 179 022 or U.K. 2 140 010 as well as U.S. Pat. Nos.6,096,329 and 6,685,954 (both assigned to Merial Ltd., Duluth, Ga.).Examples of IGRs suitable for use include but are not limited tomethoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron, lufenuron,novaluron, pyrethroids, formamidines and1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

An anthelmintic agent that can be combined with the compound of theinvention to form a composition can be a benzenedisulfonamide compound,which includes but is not limited to clorsulon; or a cestodal agent,which includes but is not limited to praziquantel, pyrantel or morantel

An parasiticidal agent that can be combined with the compound of theinvention to form a composition can be a biologically active peptide orprotein including, but not limited to, depsipeptides, which act at theneuromuscular junction by stimulating presynaptic receptors belonging tothe secretin receptor family resulting in the paralysis and death ofparasites. In one embodiment of the depsipeptide, the depsipeptide isemodepside.

An insecticidal agent that can be combined with the compound of theinvention to form a composition can be a spinosyn (e.g. spinosad) or asubstituted pyridylmethyl derivative compound such as imidacloprid.Agents of this class are described above, and for example, in U.S. Pat.No. 4,742,060 or in EP 0 892 060. It would be well within the skilllevel of the practitioner to decide which individual compound can beused in the inventive formulation to treat a particular infection of aninsect. For endoparasites, parasiticides which can be combined includebut are not limited to pyrantel, morantel, the benzimidazoles (includingalbendazole, cambendazole, thiabendazole, fenbendazole, febantel,oxfendazole, oxibendazole, triclabendazole mebendazole and netobimin),levamisole, closantel, rafoxanide, nitroxynil, disophenol andparaherquamide. For ectoparasites, insecticides which can be combinedalso include but are not limited to pyrethoids, organophosphates andneonicotinoids such as imidacloprid, as well as compounds such asmetaflumizone, amitraz and ryanodine receptor antagonists.

Where appropriate the anthelmintic, parasiticidal and insecticial agentmay also be selected from the group of compounds described above assuitable for agrochemical use.

In general, the additional pesticidal agent is included in a dose ofbetween about 0.1 μg and about 10 mg. In one embodiment of theinvention, the additional pesticidal agent is included in a dose ofbetween about 1 μg and about 10 mg. In another embodiment of theinvention, the additional pesticidal agent is included in a dose ofabout 5 to about 200 μg/kg of weight of animal. In yet anotherembodiment of the invention, the additional pesticidal agent is includedin a dose between about 0.1 to about 10 mg/kg of weight of animal. Instill another embodiment of the invention, the additional pesticidalagent is included in a dose between about 0.5 to 50 mg/kg.

The proportions, by weight, of the aryloazol-2-yl-cyanoethylaminocompound and the additional pesticidal agent are for example betweenabout 5/1 and about 10,000/1. However, one of ordinary skill in the artwould be able to select the appropriate ratio ofaryloazol-2-yl-cyanoethylamino compound and the additional pesticidalagent for the intended host and use thereof.

Another aspect of the invention is the process of making thearyloazol-2-yl-cyanoethylamino compounds of the invention.

EXAMPLES

All temperatures are given in degrees Centigrade; room temperature means20 to 25° C. Reagents were purchased from commercial sources or preparedfollowing literature procedures.

DCM=dichloromethane

THF=tetrahydrofuran

MeOH=methanol

EtOH=ethanol

EA=ethyl acetate

DMF=dimethylformamide

AcOH=acetic acid

TFA=trifluoroacetic acid

TEA=triethylamine

DIEA=diisopropylethylamine

Proton and fluorine magnetic resonance (respectively 1H NMR and 19F NMR)spectra were recorded on a Varian INOVA NMR spectrometer [400 MHz (1H)or 500 MHz (1H) and 377 MHz (19F)]. All spectra were determined in thesolvents indicated. Chemical shifts are reported in ppm downfield oftetramethylsilane (TMS), referenced to the residual proton peak of therespective solvent peak for 1H NMR. Interproton coupling constants arereported in Hertz (Hz).

LC-MS spectra were either obtained using a Thermofinnigan AQA MS ESIinstrument, using a Phenomenex Aqua 5 micron C18 125A 50×4.60 mm columnand a linear gradient from 55% methanol: 1% acetonitrile in water to100% methanol over 3 minutes. 100% methanol was maintained for 2minutes. Alternatively, LCMS spectra were obtained using an Agilent1200SL HPLC equipped with a 6130 mass spectrometer operating withelectrospray ionization; chromatographic data were obtained using aShimadzu Shim-pack XR-ODS, 3.0×30 mm, 2.2 micron particle size columnand a water:methanol gradient from 15% methanol to 95% methanol in 2.2minutes under a 1.5 mL/min flow; a hold at 95% methanol was applied atthe end of the gradient for 0.8 minutes; and both water and methanolmobile phases contained 0.1% formic acid.

General Synthetic Procedures

The compounds of formula (I) may be prepared by the application oradaptation of known methods (i.e. methods heretofore used or describedin the chemical literature).

For example, compounds of formula (I) are obtainable by a processwherein compound (II) is reacted with compound (III) wherein R₃, R₄, R₅,R₆, R₇, P, Q, V, W, X, Y, Z, and a are as defined above for thecompounds of formula (I) and T is a leaving group such as a halogenatom, methanesulfonyl, trifluoromethanesulfonyl, toluenesulfonyl and thelike.

The reaction is generally carried out in the presence of a base in asolvent.

The base to be used in this reaction includes, for example but notlimited to, inorganic bases such as sodium carbonate, potassiumcarbonate and the like, organic bases such as dimethylaminopyridine,triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undeceneand the like.

The solvent to be used in the reaction includes, for example but notlimited to, ethers such as diethylether, tetrahydrofuran and the like,halogenated hydrocarbon such as such as methylene chloride, chloroform,1,2-dichloroethane and the like.

The reaction temperature is usually in the range of −78° C. to 150° C.,preferably in the range of −20° C. to 80° C. and the reaction time isusually in the range of 1 to 72 hours.

After completion of the reaction, the compounds of formula (I) can beisolated by employing conventional methods such as adding the reactionmixture to water, extracting with an organic solvent, concentrating theextract and the like. The isolated compound of formula (I) can bepurified by a technique such as chromatography, recrystallization andthe like, if necessary.

The compounds of formula (Ia) may be prepared by the application oradaptation of known methods of amide formation (i.e. methods heretoforeused or described in the chemical literature).

Many procedures are available for forming amide bonds between an aminederivative such as the α-amino nitrile derivatives of formula (II) and acarboxylic acid with the use of coupling agents. Procedures have beendeveloped which use reagents such as carbodiimides as amide couplingagents. These carbodiimides include for example dicyclohexylcarbodiimide(DCC), diisopropylcarbodiimide (DIC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) andthe like. Catalysts such as 1-hydroxybenzotriazole (HOBT) andderivatives thereof have also been used. A summary of such methods isfound in “Comprehensive Organic Transformations”, R. C. Larock, VCHPublishers (1989) pp. 972-972. An overview of such transformations isalso available in “March's Advanced Organic Chemistry: Reactions,Mechanisms, and Structure (Sixth Edition)”, Michael B. Smith and JerryMarch, Wiley-Interscience Publishers, (2007), pp 1431-1434.

Another general reaction for the preparation of amides is the treatmentof acyl halides with amine. Such a transformation is well known to thoseskilled in the art and an overview of such transformations is availablein “March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure (Sixth Edition)”, Michael B. Smith and Jerry March,Wiley-Interscience Publishers, (2007), pp 1427-1429.

The α-amino nitrile derivatives of formula (II) can be prepared in onestep by the treatment of carbonyl compounds of general formula (IV) witha suitable cyanide source such as sodium cyanide, potassium cyanide,trimethylsilyl cyanide and the like, with amines of general formulaR₆—NH₂ such as ammonia, methyl amine and the like and generally inpresence of ammonium salt such as ammonium chloride and the like. Thoseskilled in the art will recognize this as the Strecker synthesis (seee.g. page 1391 in “March's Advanced Organic Chemistry: Reactions,Mechanisms, and Structure (Sixth Edition)”, Michael B. Smith and JerryMarch, Wiley-Interscience Publishers, (2007).

The carbonyl compounds of formula (IV) can be prepared by treatment of aNH-arylo-azole of general formula (V) with compound of general formula(VI) wherein, R₁, R₂, R₃, R₄, R₅, R₇, P, Q, V, W, X, Y, a, m and n areas defined above for the compounds of formula (I) and T is a leavinggroup such as a halogen atom, methanesulfonyl, trifluoromethanesulfonyl,toluenesulfonyl and the like.

The reaction is generally carried out in the presence of a base in asolvent.

The base to be used in this reaction includes, for example but notlimited to, inorganic bases such as sodium carbonate, potassiumcarbonate and the like, organic bases such as dimethylaminopyridine,triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undeceneand the like. The solvent to be used in the reaction includes, forexample but not limited to, acetone, ethers such as diethylether,tetrahydrofuran and the like, halogenated hydrocarbon such as such asmethylene chloride, chloroform, 1,2-dichloroethane and the like.

The reaction temperature is usually in the range of −78° C. to 150° C.,preferably in the range of −20° C. to 80° C. and the reaction time isusually in the range of 1 to 72 hours.

After completion of the reaction, the compounds of formula (IV) can beisolated by employing conventional methods such as adding the reactionmixture to water, extracting with an organic solvent, concentrating theextract and the like. The isolated compound of formula (IV) can bepurified by a technique such as chromatography, recrystallization andthe like, if necessary.

The 2H—NH-arylo-azole of formula (Va), (formula (V) with P=N), aregenerally represented as their tautomeric structure 1H—NH-arylo-azole(Vb). Specifically, 2H-benzotriazole of formula (Vc) and 2H-indazole offormula (Ve) are generally represented as their alternative tautomericforms, respectively 1H-benzotriazole of formulas (Vd) or (Ve) and1H-indazole of formula (Vg).

A discussion on tautomerism of heterocycles can be found in “TheTautomerism of Heterocycles, Advances in Heterocyclic ChemistrySupplement 1”, eds. José Elguero, Claude Marzin, Alan R. Katritzky andPaolo Linda, Academic Press Publishers, (1976).

When carbonyl compounds of formula (IVa) were prepared by treatment of a1H—NH-arylo-azole of general formula (Va) with compound of generalformula (VI), regioisomer carbonyl compounds of formula (IVb) were alsousually obtained. Those could be separated from desired carbonylcompounds of formula (IVa) by standard technique of purification knownby persons skilled in the art such as, but not limited to, liquidchromatography using normal phase or reverse phase silica column andcrystallization.

Those 1H—NH-arylo-azole compounds of general formula (Va) notcommercially available can be prepared by the application or adaptationof known methods (i.e. methods heretofore used or described in thechemical literature).

For example, a general method of preparation of 1H-benzotriazole offormula (Vd) or (Ve) wherein, R₁, R₂, V, W, X, Y, m and n are as definedabove for the compounds of formula (I) can be found in OrganicSynthesis, Coll. Vol. 3, p. 106 (1955) and in Journal of HeterocyclicChemistry, volume 22, (1985), pp. 1165-1167. Halogenation of1H-benzotriazole of formula (Vd) or (Ve) can be achieved by adaptingprocedures described in the literature such as ones described by R. H.Wiley and K. F. Hussung in Journal of the American Chemical Society,(1957), pages 4395-4400 and by K. Kopańska et al. in Bioorganic &Medicinal Chemistry, volume 13 (2005) page 3601 and in Bioorganic &Medicinal Chemistry, volume 12 (2004), pages 2617-2624.

A general method of preparation of 1H-indazole of formula (Vg) wherein,R₁, R₂, V, W, X, Y, m and n are as defined above for the compounds offormula (I) was reported in the literature by R. A. Bartsch and II-WooYang in Journal of Heterocyclic Chemistry, volume 21, (1984), pp.1063-1164 and recently by the team of Valérie Collot and Sylvain Raultin Bioorganic & Medicinal Chemistry Letters, volume 11 (2001), pages1153-1156 and volume 17 (2007), pages 3177-3180.

In one embodiment of the invention, carbonyl compounds of formula (IVa),wherein Q is alkoxymethylene (Q=C—OR₁₃) or methylene (Q=CH), are formedby oxidation of the alcohol compounds of formula (VIIa).

Such a transformation is well known to those skilled in the art, asummary of such methods is found in “Comprehensive OrganicTransformations”, VCH Publishers, (1989), R. C. Larock, pp. 604-614. Forexample, it can be realized with dimethylsulfoxide-based reagents suchas reacting oxalyl chloride with dimethylsulfoxide at low temperature,those skilled in the art will recognize this as the Swern oxidation. Itcan also be realized by nitroxyl radical,2,2,6,6-tetramethylpiperidine-1-oxyl free radical (TEMPO) and relatedreagents and with hypervalent iodine reagents such as the so calledDess-Martin Periodinane reagent (see e.g. page 1715-1728, “Oxidation orDehydrogenation of Alcohols to Aldehydes and Ketones” in “March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure (SixthEdition)”, Michael B. Smith and Jerry March, Wiley-IntersciencePublishers, (2007)). The solvent to be used in the reaction includes,for example but not limited to, ethers such as diethylether,tetrahydrofuran and the like, halogenated hydrocarbon such as such asmethylene chloride, chloroform, 1,2-dichloroethane and the like. Thereaction temperature is usually in the range of −78° C. to 150° C.,preferably in the range of −78° C. to 50° C. and the reaction time isusually in the range of 1 to 72 hours.

In another embodiment of the invention, free alcohol compounds offormula (VIIa), wherein Q is alkoxymethylene (Q=C—OR₁₃) or methylene(Q=CH), are formed by cleavage of a protecting group on thecorresponding protected alcohol compounds of formula (VIIIa) wherein R₁₂is a hydroxyl protecting group. Hydroxyl protecting group to be used inthe reaction includes, for example but not limited to, ethers, such aspara-methoxybenzyl ether, and silyl ethers, such astert-butyldimethylsilyl ether, (see e.g. “Protection for the hydroxylgroup” pages 16-299 in “Protective Groups in Organic Synthesis (FourthEdition)”, eds. Peter G. M. Wuts and Theodora W. Greene,Wiley-Interscience Publishers, (2007)).

In another embodiment of the invention, compounds of formula (VIIIb) areformed by treating compounds of formula (IXa) with alcohol of formulaR₁₃—OH and a base such as, but not limited to, potassium hydroxide,sodium hydroxide and the like.

The synthesis of 3-alkoxy-2-substituted 2H-indazoles has been describedin the chemical literature such as in Journal of Organic Chemistry,2006, 71, 2687-2689 (“N,N-Bond-Forming Heterocyclization: Synthesis of3-Alkoxy-2H-indazoles” by A. D. Mills, M. Z. Nazer, M. J. Haddadin andM. J. Kurth) and in Journal of Combinatorial Chemistry, 2007, 9, 171-177(“Synthesis of a Library of2-Alkyl-3-alkyloxy-2H-indazole-6-carboxamides” by A. D. Mills, P.Maloney, E. Hassanein, M. J. Haddadin and M. J. Kurth). However none ofthe foregoing publications describe the synthesis of compound of formula(VIIIb).

In another embodiment of the invention, compounds of formula (VIIIc) areformed by heterocyclization of compounds of formula (IXa) when treatedwith a reducing agent such as zinc.

The synthesis of 2-substituted 2H-indazoles from 2-nitrobenzylaminesderivatives has been described in the chemical literature such as inSynlett, 2007, 16, 2509-2512 (“A Novel and Efficient Synthesis of2-Aryl-2H-indazoles via SnCl₂-Mediated Cyclization of2-Nitrobenzylamines” by Da-Qing Shi et al), in Journal of the ChemicalSociety, Perkin Transactions 1, 1973, 3, 319-324 (“Pyrazolopyridines.Part II. Preparation of 3-Substituted2-Aryl-2H-pyrazolo[4,3-b]pyridines. Acid-catalysed Cyclisation of2-Arylamino-methyl-3-nitropyridines” by H. E. Foster and J. Hurst) andin Tetrahedron, 1998, 54, 3197-3206 (“2-Substituted Indazoles fromElectrogenerated Ortho-nitrosobenzylamines” by B. A. Frontana-Uribe andC. Moinet). However none of the foregoing publications describe thesynthesis of compound of formula (VIIIc).

In another embodiment of the invention, compounds of formula (VIIId) areformed by reacting aldehydes of formula (Xa) with compounds of formula(XI) in presence of a reducing agent such as, but not limited to, sodiumcyanoborohydride, sodium borohydride, sodium triacetoxyborohydride,L-Selectride® (lithium tri-sec-butyl(hydrido)borate), decaborane and thelike.

The solvent to be used in the reaction includes, for example but notlimited to, ethers such as diethylether, tetrahydrofuran and the like,halogenated hydrocarbon such as such as methylene chloride, chloroform,1,2-dichloroethane and the like. The reaction temperature is usually inthe range of −78° C. to 150° C., preferably in the range of 0° C. to 80°C. and the reaction time is usually in the range of 1 to 72 hours.

The compounds of formula (IXa) can be prepared by treating aldehydes offormula (X) with compounds of formula (XI) and a reducing agent such as,but not limited to, sodium cyanoborohydride, sodium borohydride, sodiumtriacetoxyborohydride, L-Selectride® (lithiumtri-sec-butyl(hydrido)borate), decaborane and the like.

Such a transformation is well known to those skilled in the art and isknown as reductive amination, a summary of such methods is found in“Comprehensive Organic Transformations”, VCH Publishers, (1989), R. C.Larock, pp. 421-425. The solvent to be used in the reaction includes,for example but not limited to, ethers such as diethylether,tetrahydrofuran and the like, halogenated hydrocarbon such as such asmethylene chloride, chloroform, 1,2-dichloroethane and the like. Thereaction temperature is usually in the range of −78° C. to 150° C.,preferably in the range of 0° C. to 80° C. and the reaction time isusually in the range of 1 to 72 hours.

Alternatively, the compounds of formula (IXa) can be prepared bytreating compounds of formula (XI) with compounds of formula (XII) whereT is a leaving group such as a halogen atom, methanesulfonyl,trifluoromethanesulfonyl, toluenesulfonyl and the like.

When not commercially available, the aldehydes of formula (X) can beprepared by oxidative cleavage of the alkene moiety of compound offormula (XIII) wherein R₁₄ and R₁₅ are independently selected from C1-C4alkylcarbonyl and C1-C4 alkyl.

Such a transformation is well known to those skilled in the art and canbe realized for example with ozone, potassium permanganate and sodiummetaperiodate. The process may be carried out optionally in a solventsuch as methylene chloride, diethylether, chloroform and generally attemperatures between about −100 and about 100° C. A summary of suchmethods is found in “Comprehensive Organic Transformations”, VCHPublishers, (1989), R. C. Larock, pp. 595-596.

The alkene compounds of formula (XIII), wherein R₁₄ and R₁₅ areindependently selected from C1-C4 alkylcarbonyl and C1-C4 alkyl, can beprepared from coupling reactions of compound of formula (XIV), whereinR₁₆ is halogen atom or trifluoromethanesulfonyl and the like, withcompound of formula (XV), wherein M is trialkyltin, boronic acid orboronate ester, and a palladium catalyst.

Such a transformation using compound of formula (XV), wherein M istrialkyltin, is known to those skilled in the art as the Stile coupling.A description of such methods is found in “March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure (Sixth Edition)”,Michael B. Smith and Jerry March, Wiley-Interscience Publishers, (2007)pp. 792-795.

The solvent to be used in the reaction includes, for example but notlimited to, ethers such as tetrahydrofuran, dioxane and the like,halogenated hydrocarbon such as such as 1,2-dichloroethane and the like,aromatic solvent such as benzene, toluene, xylene and the like. Thereaction temperature is usually in the range of 0° C. to 200° C.,preferably in the range of 20° C. to 120° C. and the reaction time isusually in the range of 1 to 72 hours.

The compounds of formula (XIVa), wherein R₁₆ is halogen atom, can beprepared from compounds of formula (XV) via formation of diazonium saltfrom corresponding aniline and treatment with cuprous halides.

Such a transformation is known to those skilled in the art as theSandmyer reaction (see e.g. “March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure (Sixth Edition)”, Michael B. Smithand Jerry March, Wiley-Interscience Publishers, (2007) pp. 984-985).

The compounds of formula (Ii); wherein V is nitrogen or C—R₈, R₁₀ ishalogen and R₂ and R₁₁ are either together or independently of eachanother, halogen or hydrogen; can be achieved by halogenation of thecorresponding precursor compound of formula (Ig-1) using electrophilichalogenating agent known in the art such as, but not limited to,N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, Selectfluor®[1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis-(tetrafluoroborate)] and the like.

The compounds of formula (Ig) wherein p is 1 or 2 can be achieved byoxidation of the corresponding precursor compound of formula (If) usingconventional oxidizers known in the art.

It will be appreciated by persons skilled in the art that, within aspectof the processes described above; the order of the synthetic stepsemployed may be varied and will depend inter alia on factors such as thenature of other functional groups present in a particular substrate, theavailability of key intermediates, and the protecting group strategy (ifany) to be adopted (see e.g. “Protective Groups in Organic Synthesis(Fourth Edition)”, eds. Peter G. M. Wuts and Theodora W. Greene,Wiley-Interscience Publishers, (2007)). Clearly, such factors will alsoinfluence the choice of reagents for use in the said synthetic steps.

Compounds of Examples 1 to 10 and 52 to 58 were Prepared According tothe General Reaction Scheme

Final ProductV=C—R₈; W=C—R₉; X=C—R₁₀; Y=C—R₁₁;Q=P=N;R₃=R₄=H; a=1; R₅=methyl, butyl or CH₂OH; R₆=HZ=C(O); R₇=p-phenyl-R

Example 1N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.001)

4-trifluoromethoxybenzoyl chloride (0.34 g) was added to a solution of2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (0.3 g)in dry DCM mixed with TEA (0.27 mL). The reaction mixture was stirred 48hours at room temperature. Silica gel was added to the reaction mixtureand solvent evaporated under reduced pressure. The resulting crudeproduct loaded on silica gel was purified by chromatography (SiO₂,heptane/EA) to afford the title compound as a white solid (0.3 g, 54%).Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=424. 1H NMR: (400 MHz,DMSO-d₆): 1.74 (s, 3H), 5.39-5.49 (m, 2H), 7.48 (dd, J=9.1, 1.9 Hz, 1H),7.51 (br d, J=8.0 Hz, 2H), 7.93 (m, 2H), 8.01 (dd, J=9.1, 0.6 Hz, 1H),8.13 (dd, J=1.9, 0.6 Hz, 1H) and 8.92 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −57.09 (s, 3F).

The starting material,2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, wasprepared as follows:

-   -   a. A mixture of 5-chloro-1H-benzotriazole (8 g), chloroacetone        (6.5 mL), potassium carbonate (9.5 g) and potassium iodide        (0.5 g) was stirred in acetone (90 mL) at room temperature for        48 hours. The reaction mixture was filtered and the filtrate        concentrated under reduced pressure to give a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        1-(5-chloro-2H-benzotriazol-2-yl)-propan-2-one as clear oil [1.8        g, 16%, Rf=0.6 (1:1 EA/heptane)]. The two other regioisomers        were also isolated,        1-(6-chloro-1H-benzotriazol-1-yl)-propan-2-one [3.8 g, 35%,        Rf=0.45 (1:1 EA/heptane)] and        1-(5-chloro-1H-benzotriazol-1-yl)-propan-2-one [3.2 g, 29%,        Rf=0.35 (1:1 EA/heptane)].    -   b. Ammonia was charged into methanol (50 mL) at −78° C. for 5        min. The solution was allowed to warm to room temperature and        was then treated with sodium cyanide (0.7 g), ammonium chloride        (0.9 g) and 1-(5-chloro-2H-benzotriazol-2-yl)-propan-2-one (2.25        g). The reaction mixture was stirred for 6 days at room        temperature before being concentrated under reduced pressure.        The residue was taken into ethyl acetate, filtered and the        filtrate concentrated under reduced pressure to give a residue        that was purified by chromatography (SiO₂, heptane/EA) to afford        2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile        as a light yellow solid (2.0 g, 79%). Rf=0.25 (1:1 EA/heptane).

Example 2N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylbenzamide(compound No 1.002)

Using a procedure similar to that described in Example 1, except using4-trifluoromethylbenzoyl chloride, the title compound was isolated as awhite solid (0.12 g, 71%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z[M+H]=408. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.40-5.52 (m, 2H),7.48 (dd, J=9.1, 1.9 Hz, 1H), 7.88-7.93 (m, 2H), 7.99 (br d, J=7.8 Hz,1H), 8.03 (d, J=0.6 Hz, 1H), 8.13 (dd, J=1.9, 0.6 Hz, 1H) and 9.04 (s,1H).

Example 3N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.003)

Using a procedure similar to that described in Example 1, except using4-trifluoromethylthiobenzoyl chloride, the title compound was isolatedas a white solid (1.4 g, 75%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z[M+H]=440. 1H NMR: (400 MHz, DMSO-d₆): 1.74 (s, 3H), 5.39-5.50 (m, 2H),7.48 (dd, J=9.1, 1.9 Hz, 1H), 7.85-7.92 (m, 4H), 8.01 (dd, J=9.1, 0.7Hz, 1H), 8.13 (dd, J=1.9, 0.6 Hz, 1H) and 9.01 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −41.93 (s, 3F).

Example 4N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide(compound No 1.032)

Using a procedure similar to that described in Example 1, except using4-phenoxybenzoyl chloride, the title compound was isolated as a whitesolid (57 mg, 65%). MS (ES): M/Z [M+H]=432. 1H NMR: (400 MHz, DMSO-d₆):1.74 (s, 3H), 5.40-5.46 (m, 2H), 7.04-7.16 (m, 4H), 7.20-7.27 (m, 1H),7.42-7.51 (m, 3H), 7.82-7.88 (m, 2H), 7.99-8.05 (m, 1H), 8.12-8.15 (m,1H,) and 8.74 (s, 1H).

4-Phenoxybenzoyl chloride was prepared by reacting 4-phenoxybenzoic acidwith oxalyl chloride.

Example 5N-[2-(2H-Benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.004)

Using a procedure similar to that described in Example 1, except using2-amino-3-(2H-benzotriazol-2-yl)-2-methylpropionitrile, the titlecompound was isolated as a white solid (0.1 g, 51%). Rf=0.55 (1:1EA/heptane). MS (ES): M/Z [M+H]=390. 1H NMR: (400 MHz, DMSO-d₆): 1.75(s, 3H), 5.39-5.49 (m, 2H), 7.45 (br s, 2H), 7.51 (d, J=8.0 Hz, 2H),7.94 (br d, J=7.5 Hz, 4H) and 8.93 (s, 1H).

2-Amino-3-(2H-benzotriazol-2-yl)-2-methylpropionitrile [1.9 g, 97%,Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similar to thatdescribed in Example 1, part a and b, except starting from1H-benzotriazole.

Example 6N-[2-(2H-Benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.005)

Using a procedure similar to that described in Example 1, except using2-amino-3-(2H-benzotriazol-2-yl)-2-methylpropionitrile, described inExample 5, and 4-trifluoromethylthiobenzoyl chloride, the title compoundwas isolated as a white solid (0.12 g, 59%). Rf=0.6 (1:1 EA/heptane). MS(ES): M/Z [M+H]=406. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.39-5.50(m, 2H), 7.46 (dd, J=6.6, 3.1 Hz, 2H), 7.85-7.95 (m, 6H) and 9.01 (s,1H).

Example 7N-[1-Cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethoxybenzamide(compound No 1.006)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5-methyl-2H-benzotriazol-2-yl)propionitrile, thetitle compound was isolated as a white solid (0.09 g, 45%). Rf=0.6 (1:1EA/heptane). MS (ES): M/Z [M+H]=404. 1H NMR: (400 MHz, DMSO-d₆): 1.73(s, 3H), 2.45 (s, 3H), 5.34-5.43 (m, 2H), 7.30 (dd, J=8.8, 1.4 Hz, 1H),7.52 (d, J=8.0 Hz, 2H), 7.68 (d, J=1.0 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H),7.90-7.97 (m, 2H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.08(s, 3F).

2-Amino-2-methyl-3-(5-methyl-2H-benzotriazol-2-yl)propionitrile [2.1 g,92%, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similar tothat described in Example 1, part a and b, except starting from5-methyl-1H-benzotriazole.

Example 8N-[1-Cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide(compound No 1.007)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5-methyl-2H-benzotriazol-2-yl)propionitrile,described in Example 7, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (0.12 g, 57%). Rf=0.65 (1:1EA/heptane). MS (ES): M/Z [M+H]=420. 1H NMR: (400 MHz, DMSO-d₆): 1.73(s, 3H), 2.45 (s, 3H), 5.34-5.44 (m, 2H), 7.30 (dd, J=8.8, 1.4 Hz, 1H),7.68 (d, J=1.0 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.84-7.94 (m, 4H) and8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −41.94 (s, 3F).

Example 9N-[2-(5-Chloro-6-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.040)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-6-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(90 mg), the title compound was isolated as a white solid (125 mg, 79%).Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=438. 1H NMR: (400 MHz,DMSO-d₆): 1.73 (s, 3H), 2.46 (s, 3H), 5.38 (d, J=13.4 Hz, 1H), 5.44 (d,J=13.3 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 7.96 (s,1H), 8.13 (s, 1H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.08(s, 3F).

2-Amino-3-(5-chloro-6-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile[2.1 g, 92%, Rf=0.2 (1:1 EA/heptane)] was prepared using a proceduresimilar to that described in Example 1, part a and b, except startingfrom 6-chloro-5-methyl-1H-benzotriazole.

Example 10N-[2-(5-Chloro-6-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.041)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-6-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(90 mg, described in Example 9) and 4-trifluoromethylthiobenzoylchloride (0.1 mL), the title compound was isolated as a white solid (152mg, 93%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=454. 1H NMR: (400MHz, DMSO-d₆): 1.73 (s, 3H), 2.46 (s, 3H), 5.38 (d, J=13.4 Hz, 1H), 5.45(d, J=13.4 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.96(s, 1H), 8.13 (s, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−41.93 (s, 3F).

Compounds of Examples 11 to 51 were Prepared According to the GeneralReaction Scheme

Final ProductV=C—R₈; W=C—R₈; X=C—R₁₀; Y=C—R₁₁;Q=P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 11N-[1-Cyano-1-methyl-2-(5-trifluoromethyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethoxybenzamide(compound No 1.008)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5-trifluoromethyl-2H-benzotriazol-2-yl)propionitrile,the title compound was isolated as a white solid (65 mg, 26%). Rf=0.6(1:1 EA/heptane). MS (ES): M/Z [M+H]=458. 1H NMR: (400 MHz, DMSO-d₆):1.76 (s, 3H), 5.47-5.57 (m, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.71 (dd,J=9.0, 1.6 Hz, 1H), 7.93 (m, 2H), 8.20 (d, J=9.0 Hz, 1H), 8.50 (br s,1H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −61.17 (s, 3F) and−57.09 (s, 3F).2-Amino-2-methyl-3-(5-trifluoromethyl-2H-benzotriazol-2-yl)propionitrile[1.2 g, 69%, Rf=0.35 (1:1 EA/heptane)] was prepared using a proceduresimilar to that described in Example 1, part a and b, except startingfrom 5-trifluoromethyl-1H-benzotriazole, that was prepared as follows:

-   -   a. A mixture of 2-nitro-4-trifluoromethylaniline (12 g) and        activated palladium on charcoal (0.6 g) in methanol was        hydrogenated with one atmosphere of hydrogen under stirring at        room temperature for one hour. The reaction mixture was filtered        through a pad of diatomaceous earth and the filtrate        concentrated under reduced pressure to give a residue. This        residue was then dissolved in acetic acid (100 mL) and water (15        mL) and cooled to 0° C. prior to adding hydrochloric acid (4 mL)        and a solution of sodium nitrite (4.4 g) in water (10 mL). The        mixture was stirred at room temperature for two hours and then        diluted with water. The resulting solid was filtered, washed        with water and dried to obtain an off-white solid (8.0 g, 73%).

Example 12N-[1-Cyano-1-methyl-2-(5-trifluoromethyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide(compound No 1.009)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5-trifluoromethyl-2H-benzotriazol-2-yl)-propionitrile,described in Example 11, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (0.16 g, 61%). Rf=0.65 (1:1EA/heptane). MS (ES): M/Z [M+H]=474. 1H NMR: (400 MHz, CHLOROFORM-d):1.88 (s, 3H), 5.39 (dd, J=112.8, 13.7 Hz, 2H), 7.38 (br s, 1H), 7.65 (d,J=9.1 Hz, 1H), 7.75-7.88 (m, 4H), 8.02 (d, J=9.0 Hz, 1H) and 8.25 (br s,1H). 19F NMR (376 MHz, CHLOROFORM-d): −63.01 (s, 3F) and −42.23 (s, 3F).

Example 13N-[1-Cyano-2-(5,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.010)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, thetitle compound was isolated as a white solid (72 mg, 28%). Rf=0.6 (1:1EA/heptane). MS (ES): M/Z [M+H]=458. 1H NMR: (400 MHz, DMSO-d₆): 1.74(s, 3H), 5.41-5.51 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.93 (d, J=8.8 Hz,2H), 8.43 (br s, 2H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−57.10 (s, 3F).

2-Amino-3-(5,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile[0.35 g, 79%, Rf=0.25 (1:1 EA/heptane)] was prepared using a proceduresimilar to that described in Example 1, part a and b, except startingfrom 5,6-dichloro-1H-benzotriazole, that was prepared as follows:

-   -   a. 4,5-Dichlorobenzene-1,2-diamine (4.8 g) was dissolved in        acetic acid (45 mL) and water (15 mL) and cooled to 0° C. prior        to adding hydrochloric acid (2 mL) and a solution of sodium        nitrite (2.8 g) in water (15 mL). The mixture was stirred at        room temperature for 30 minutes and then diluted with water. The        resulting solid was filtered, washed with water and dried. The        resulting crude product was dissolved in hot ethanol. Any        residual solid was filtered off and the filtrate let cooled        down. Addition of water formed a solid that was filtered, washed        with water and dried to give a tan solid (2.8 g, 55%).

Example 14N-[1-Cyano-2-(5,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.011)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 13, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (90 mg, 34%). MS (ES): M/Z[M+H]=474. 1H NMR: (400 MHz, DMSO-d₆): 1.74 (s, 3H), 5.41-5.51 (m, 2H),7.82-7.91 (m, 4H), 8.41 (br s, 2H) and 9.00 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −41.94 (s, 3F).

Example 15N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.012)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, thetitle compound was isolated as a white solid (83 mg, 33%). Rf=0.65 (1:1EA/heptane). MS (ES): M/Z [M+H]=458. 1H NMR: (400 MHz, DMSO-d₆): 1.75(s, 3H), 5.40-5.55 (m, 2H), 7.47 (d, J=8.25 Hz, 2H), 7.69 (dd, J=1.5,0.8 Hz, 1H), 7.92 (d, J=8.8 Hz, 2H), 8.13 (d, J=1.6 Hz, 1H) and 8.87 (s,1H). 19F NMR (376 MHz, DMSO-d₆): −57.19 (s, 3F).

2-Amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile[0.35 g, 63%, Rf=0.35 (1:1 EA/heptane)] was prepared using a proceduresimilar to that described in Example 1, part a and b, except startingfrom 5,7-dichloro-1H-benzotriazole. 5,7-Dichloro-1H-benzotriazole (11 g,99%) was prepared using a procedure similar to that described in Example11, part a, except starting from 2,4-dichloro-6-nitroaniline (12 g).

Example 16N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.013)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 15, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (50 mg, 20%). Rf=0.7 (1:1EA/heptane). MS (ES): M/Z [M+H]=475. NMR: (400 MHz, DMSO-d₆): 1.75 (s,3H), 5.40-5.56 (m, 2H), 7.65 (m, 1H), 7.79-7.95 (m, 4H), 8.10 (m, 1H)and 8.95 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.05 (s, 3F).

Example 17N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]biphenyl-4-carboxamide(compound No 1.046)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 15, and 4-biphenyl carbonyl chloride, the titlecompound was isolated as a white solid (32 mg). MS (ES): M/Z [M+H]=450.NMR: (400 MHz, DMSO-d₆): 1.78 (s, 3H), 5.45 (d, J=13.3 Hz, 1H), 5.55 (d,J=13.3 Hz, 1H), 7.43 (m, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.70-7.78 (m, 3H),7.81 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.18 (d, J=1.6 Hz, 1H)and 8.83 (s, 1H).

Example 18N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-tert-butylbenzamide(compound No 1.053)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 15, and 4-tert-butylbenzoyl chloride, the titlecompound was isolated as a white solid (80 mg). MS (ES): M/Z [M+H]=430.NMR: (400 MHz, DMSO-d₆): 1.30 (s, 9H), 1.75 (s, 3H), 5.47 (q, J=17.8 Hz,2H), 5.51 (d, J=8.3 Hz, 2H), 7.70-7.76 (m, 3H), 8.18 (d, J=1.5 Hz, 1H)and 8.70 (br s, 1H).

Example 19N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.014)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile,the title compound was isolated as a white solid (0.66 g, 82%). Rf=0.7(1:1 EA/heptane). MS (ES): M/Z [M+H]=492. 1H NMR: (400 MHz, DMSO-d₆):1.77 (s, 3H), 5.46-5.67 (m, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.89-7.96 (m,2H), 8.56 (br s, 1H) and 8.87 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−61.07 (s, 3F) and −57.15 (s, 3F).

2-Amino-3-(4-chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile[1.7 g, 89%, Rf=0.35 (1:1 EA/heptane)] was prepared using a proceduresimilar to that described in Example 1, part a and b, except startingfrom 7-chloro-5-trifluoromethyl-1H-benzotriazole.7-Chloro-5-trifluoromethyl-1H-benzotriazole (4.6 g, 99%) was preparedusing a procedure similar to that described in Example 11, part a,except starting from 4-amino-3-chloro-5-nitrobenzotrifluoride (5 g).

Example 20N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.015)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 19, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (0.45 g, 90%). Rf=0.6 (1:1EA/heptane). MS (ES): M/Z [M+H]=508. 1H NMR: (400 MHz, DMSO-d₆): 1.77(s, 3H), 5.49-5.65 (m, 2H), 7.84-7.93 (m, 5H), 8.56 (d, J=1.1 Hz, 1H)and 8.95 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −61.09 (s, 3F) and −42.03(s, 3F).

Example 21N-[1-Cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.016)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-cyano-2H-benzotriazol-2-yl)-2-methylpropionitrile, thetitle compound was isolated as a white solid (0.25 g, 45%). Rf=0.45 (1:1EA/heptane). MS (ES): M/Z [M+H]=415. 1H NMR: (400 MHz, DMSO-d₆): 1.76(s, 3H), 5.46-5.59 (m, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.76 (dd, J=8.8, 1.4Hz, 1H), 7.89-7.96 (m, 2H), 8.17 (dd, J=8.9, 0.9 Hz, 1H), 8.77 (m, 1H)and 8.93 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.11 (s, 3F).

2-Amino-3-(5-cyano-2H-benzotriazol-2-yl)-2-methylpropionitrile [0.85 g,75%, Rf=0.15 (1:1 EA/heptane)] was prepared using a procedure similar tothat described in Example 1, part a and b, except starting from5-cyano-1H-benzotriazole. 5-Cyano-1H-benzotriazole (5.7 g, 65%) wasprepared using a procedure similar to that described in Example 11, parta, except starting from 4-amino-3-nitrobenzonitrile (10 g).

Example 22N-[1-Cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.017)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-cyano-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 21, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (0.46 g, 81%). Rf=0.45 (1:1EA/heptane). MS (ES): M/Z [M+H]=431. 1H NMR: (400 MHz, DMSO-d₆): 1.76(s, 3H), 5.46-5.59 (m, 2H), 7.76 (dd, J=8.9, 1.3 Hz, 1H), 7.84-7.93 (m,4H), 8.18 (d, J=8.9 Hz, 1H), 8.78 (br s, 1H) and 9.01 (br s, 1H). 19FNMR (376 MHz, DMSO-d₆): −41.93 (s, 3F).

Example 23N-[2-(4,6-Bis(trifluoromethyl)-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.018)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-bis(trifluoromethyl)-2H-benzotriazol-2-yl)-2-methylpropionitrile,the title compound was isolated as a white solid (0.41 g, 88%). Rf=0.6(1:1 EA/heptane). MS (ES): M/Z [M+H]=526. 1H NMR: (400 MHz, DMSO-d₆):1.79 (s, 3H), 5.61 (dd, J=55.9, 13.3 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H),7.88-7.91 (m, 2H), 8.13 (s, 1H), 8.83 (s, 1H) and 8.98 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −57.18 (s, 3F), −61.00 (s, 3F) and −61.59 (s, 3F).

2-Amino-3-(4,6-bis(trifluoromethyl)-2H-benzotriazol-2-yl)-2-methylpropionitrile[1.5 g, 77%, Rf=0.3 (1:1 EA/heptane)] was prepared using a proceduresimilar to that described in Example 1, part a and b, except startingfrom 5,7-bis(trifluoromethyl)-2H-benzotriazole.5,7-Bis(trifluoromethyl)-1H-benzotriazole (5.2 g, 99%) was preparedusing a procedure similar to that described in Example 13, part a,except starting from 3,5-bis(trifluoromethyl)-1,2-phenylenediamine (5g).

Example 24N-[2-(4,6-Bis(trifluoromethyl)-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.019)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-bis(trifluoromethyl)-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 23, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (0.40 g, 83%). Rf=0.7 (1:1EA/heptane). MS (ES): M/Z [M+H]=542. 1H NMR: (400 MHz, DMSO-d₆): 1.79(s, 3H), 5.62 (dd, J=60.6, 13.3 Hz, 2H), 7.76-7.97 (m, 4H), 8.13 (s,1H), 8.92 (s, 1H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −61.62(s, 3F), −61.04 (s, 3F) and −42.10 (s, 3F).

Example 25N-[2-(5-Bromo-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.020)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-bromo-2H-benzotriazol-2-yl)-2-methylpropionitrile, thetitle compound was isolated as a white solid (0.36 g, 72%). Rf=0.65 (1:1EA/heptane). MS (ES): M/Z [M+H]=468. 1H NMR: (400 MHz, DMSO-d₆): 1.74(s, 3H), 5.44 (dd, J=26.8, 13.3 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.58(dd, J=9.1, 1.8 Hz, 1H), 7.91-7.96 (m, 2H), 7.96 (dd, J=9.1, 0.5 Hz,1H), 8.29 (dd, J=1.7, 0.5 Hz, 1H) and 8.92 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −57.09 (s, 3F).

2-Amino-3-(5-bromo-2H-benzotriazol-2-yl)-2-methylpropionitrile [1.7 g,93%, Rf=0.35 (1:1 EA/heptane)] was prepared using a procedure similar tothat described in Example 1, part a and b, except starting from5-bromo-1H-benzotriazole. 5-bromo-1H-benzotriazole was prepared using aprocedure similar to that described in Example 13, part a, exceptstarting from 4-bromo-1,2-diamino benzene.

Example 26N-[2-(5-Bromo-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.021)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-bromo-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 25, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (0.45 g, 87%). Rf=0.65 (1:1EA/heptane). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, DMSO-d₆): 1.74(s, 3H), 5.36-5.53 (m, 2H), 7.58 (dd, J=9.1, 1.8 Hz, 1H), 7.84-7.92 (m,4H), 7.95 (dd, J=9.1, 0.5 Hz, 1H), 8.29 (dd, J=1.7, 0.6 Hz, 1H) and 9.00(s, 1H). 19F NMR (376 MHz, DMSO-d₆): −41.93 (s, 3F).

Example 27N-[-2-(6-Chloro-4-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.033)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile,the title compound was isolated as a white solid (192 mg, 55%). MS (ES):M/Z [M+H]=438. 1H NMR: (400 MHz, DMSO-d₆): 1.74 (s, 3H), 2.47 (s, 3H),5.35-5.51 (m, 2H), 7.27 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.88-7.95 (m,3H) and 8.84 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.12 (s, 3F).

2-Amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(0.4 g, 67%) was prepared using a procedure similar to that described inExample 1, part a and b, except starting from5-chloro-7-methyl-1H-benzotriazole. 5-Chloro-7-methyl-1H-benzotriazole(4.35 g, 97%) was prepared using a procedure similar to that describedin Example 11, part a, except starting from4-chloro-2-methyl-6-nitroaniline (5 g).

Example 28N-[2-(6-Chloro-4-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.034)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 27, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (233 mg, 64%). MS (ES): M/Z[M+H]=454. NMR: (400 MHz, DMSO-d₆): 1.74 (s, 3H), 2.47 (s, 3H), 5.44(dd, J=57.5, 13.3 Hz, 2H), 7.27 (s, 1H), 7.79-7.99 (m, 5H) and 8.92 (s,1H). 19F NMR (376 MHz, DMSO-d₆): −42.01 (s, 3F).

Example 29N-[2-(6-Chloro-4-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide(compound No 1.039)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(60 mg, described in Example 27) and 4-phenoxybenzoyl chloride (0.067mL), the title compound was isolated as a white solid (90 mg, 84%). MS(ES): M/Z [M+H]=446. NMR: (400 MHz, DMSO-d₆): 1.73 (s, 3H), 2.47 (s,3H), 5.38 (d, J=13.3 Hz, 1H), 5.45 (d, J=13.3 Hz, 1H), 7.08 (t, J=8.25Hz, 4H), 7.23 (t, 1H), 7.28 (s, 1H), 7.45 (t, 2H), 7.84 (d, J=8.79 Hz,2H), 7.91 (m, 1H) and 8.68 (s, 1H).

4-Phenoxybenzoyl chloride was prepared by reacting 4-phenoxybenzoic acidwith oxalyl chloride.

Example 30N-[1-Cyano-1-methyl-2-(5-trifluoromethoxy-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethoxybenzamide(compound No 1.035)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-trifluoromethoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile(100 mg), the title compound was isolated as a white solid (140 mg,85%). MS (ES): M/Z [M+H]=474. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H),5.44 (d, J=13.3 Hz, 1H), 5.51 (d, J=13.4 Hz, 1H), 7.45-7.52 (m, 3H),7.93 (d, J=8.8 Hz, 2H), 8.06 (br s, 1H), 8.12 (d, 1H, J=9.9 Hz) and 8.89(s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.42 (s, 3F) and −57.11 (s, 3F).

2-Amino-3-(5-trifluoromethoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile(0.24 g) was prepared using a procedure similar to that described inExample 1, part a and b, except starting from5-trifluoromethoxy-1H-benzotriazole (3.2 g).5-Trifluoromethoxy-1H-benzotriazole (3.4 g, 74%) was prepared using aprocedure similar to that described in Example 11, part a, exceptstarting from 2-nitro-4-trifluoromethoxyaniline (5 g).

Example 31N-[1-Cyano-1-methyl-2-(5-trifluoromethoxy-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide(compound No 1.036)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-trifluoromethoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile(100 mg, described in Example 30) and 4-trifluoromethylthiobenzoylchloride (0.12 mL), the title compound was isolated as a white solid(142 mg, 83%). MS (ES): M/Z [M+H]=490. 1H NMR: (400 MHz, CHLOROFORM-d):1.75 (s, 3H), 5.48 (d, J=13.4 Hz, 1H), 5.52 (d, J=13.3 Hz, 1H), 7.47 (d,J=10.6 Hz, 1H), 7.85-7.91 (m, 4H), 8.05 (br s, 1H), 8.12 (d, 1H, J=9.3Hz) and 8.98 (br s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −57.43 (s, 3F)and −41.96 (s, 3F).

Example 32N-[2-(6-Chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.037)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(100 mg), the title compound was isolated as a white solid (148 mg,91%). MS (ES): M/Z [M+H]=492. 1H NMR: (400 MHz, DMSO-d₆): 1.77 (s, 3H),2.47 (s, 3H), 5.46 (d, J=13.2 Hz, 1H), 5.60 (d, J=13.4 Hz, 1H), 7.49 (d,J=8.0 Hz, 2H), 7.89 (d, J=8.8 Hz, 2H), 7.96 (s, 1H), 8.56 (s, 1H) and8.85 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −61.51 (s, 3F) and −57.16 (s,3F).

2-Amino-3-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(0.82 g) was prepared using a procedure similar to that described inExample 1, part a and b, except starting from5-chloro-7-trifluoromethyl-1H-benzotriazole (2.5 g).5-Chloro-7-trifluoromethyl-1H-benzotriazole (2.5 g, 55%) was preparedusing a procedure similar to that described in Example 11, part a,except starting from 2-amino-5-chloro-3-nitrobenzotrifluoride (5 g).

Example 33N-[2-(6-Chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.038)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(100 mg, described in Example 32) and 4-trifluoromethylthiobenzoylchloride (0.12 mL), the title compound was isolated as a white solid(142 mg, 85%). MS (ES): M/Z [M+H]=508. NMR: (400 MHz, DMSO-d₆): 1.77 (s,3H), 2.47 (s, 3H), 5.46 (d, J=13.3 Hz, 1H), 5.62 (d, J=13.3 Hz, 1H),7.82-7.88 (m, 4H), 7.96 (s, 1H), 8.57 (s, 1H) and 8.93 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −42.05 (s, 3F) and −61.51 (s, 3F).

Example 34N-[2-(6-Chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide(compound No 1.042)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(100 mg, described in Example 32) and 4-phenoxybenzoyl chloride (0.10mL), the title compound was isolated as a white solid (95 mg, 58%).Rf=0.75 (1:1 EA/heptane). MS (ES): M/Z [M+H]=500. NMR: (400 MHz,DMSO-d₆): 1.76 (s, 3H), 2.47 (s, 3H), 5.47 (d, J=13.3 Hz, 1H), 5.57 (d,J=13.3 Hz, 1H), 7.04-7.12 (m, 4H), 7.22 (t, J=7.4 Hz, 1H), 7.97 (s, 1H),8.57 (s, 1H) and 8.69 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −61.41 (s,3F).

4-Phenoxybenzoyl chloride was prepared by reacting 4-phenoxybenzoic acidwith oxalyl chloride.

Example 35N-[2-(4-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.043)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (100mg), the title compound was isolated as a white solid (142 mg, 80%).Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=424. 1H NMR: (400 MHz,DMSO-d₆): 1.77 (s, 3H), 5.43 (d, J=13.4 Hz, 1H), 5.54 (d, J=13.4 Hz,1H), 7.46 (t, 1H), 7.50 (d, J=7.9 Hz, 2H), 7.59 (d, J=6.8 Hz, 1H),7.91-7.97 (m, 3H) and 8.90 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.12(s, 3F).

2-Amino-3-(4-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (0.3 g)was prepared using a procedure similar to that described in Example 1,part a and b, except starting from 7-chloro-1H-benzotriazole (1.0 g).7-chloro-1H-benzotriazole (1.0 g, 23%) was prepared using a proceduresimilar to that described in Example 11, part a, except starting from3-chloro-2-nitroaniline (5 g).

Example 36N-[2-(4-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.044)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg,described in Example 35) and 4-trifluoromethylthiobenzoyl chloride (0.1mL), the title compound was isolated as a white solid (130 mg, 70%).Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=440. NMR: (400 MHz,DMSO-d₆): 1.75 (s, 3H), 5.43 (d, J=13.3 Hz, 1H), 5.55 (d, J=13.4 Hz,1H), 7.46 (t, J=8.0 Hz, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.75-7.95 (m, 5H)and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −41.98 (s, 3F).

Example 37N-[2-(4-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide(compound No 1.045)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg,described in Example 35) and 4-phenoxybenzoyl chloride (0.10 mL), thetitle compound was isolated as a white solid (70 mg, 38%). Rf=0.7 (1:1EA/heptane). MS (ES): M/Z [M+H]=432. NMR: (400 MHz, DMSO-d₆): 1.75 (s,3H), 5.43 (d, J=13.3 Hz, 1H), 5.50 (d, J=13.3 Hz, 1H), 7.04-7.10 (m,4H), 7.22 (t, J=7.4 Hz, 1H), 7.43-7.48 (m, 3H), 7.59 (d, J=6.6 Hz, 1H),7.84 (d, J=8.9 Hz, 2H), 7.94 (d, J=8.0 Hz, 1H) and 8.73 (s, 1H).

4-Phenoxybenzoyl chloride was prepared by reacting 4-phenoxybenzoic acidwith oxalyl chloride.

Example 38N-[2-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.060)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-bromo-6-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile(1.0 g), the title compound was isolated as a white solid (1.5 g, 90%).Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=502. 1H NMR: (400 MHz,DMSO-d₆): 1.75 (s, 3H), 5.42 (d, 1H), 5.53 (d, 1H), 7.51 (d, J=8.0 Hz,2H), 7.86 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.8 Hz, 2H), 8.20 (d, J=1.6 Hz,1H) and 8.88 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(4-bromo-6-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrilewas prepared using a procedure similar to that described in Example 1,part a and b, except starting from 7-bromo-5-chloro-1H-benzotriazole.7-Bromo-5-chloro-1H-benzotriazole (7.6 g, 99%) was prepared using aprocedure similar to that described in Example 13, part a, exceptstarting from 3-bromo-5-chloro-1,2-diaminobenzene that was prepared asfollows:

-   -   a. A mixture of 4-chloro-2-nitroaniline (10 g) and        N-bromosuccinimide (11.3 g) in acetonitrile (200 mL) was heated        at 70° C. overnight. The mixture was concentrated under reduced        pressure and then poured into water and let stirred at room        temperature for one hour. The resulting solid was filtered,        washed with water and dried. The resulting crude product loaded        on silica gel was purified by chromatography (SiO₂, heptane/EA)        to afford 2-bromo-4-chloro-6-nitroaniline as a yellow solid        (11.5 g, 79%). Rf=0.6 (3:7 EA/heptane).    -   b. To a rapidly stirred suspension of iron powder (1.1 g) in        ethanol (10 mL) was added concentrated hydrochloric acid        (2.5 ml) and the mixture heated at 65° C. After 4 hours, a 25%        aqueous solution of ammonium chloride was added (4 mL) followed        by slow addition of a solution of        2-bromo-4-chloro-6-nitroaniline (1 g) in ethanol. After 3 hours,        the mixture was allowed to cool down to room temperature and        Celite® filter agent was added directly to the mixture. The        suspension was filtered through a plug of Celite® filter agent.        The filtrate was concentrated under reduced pressure, dissolved        in ethyl acetate and filtered through a plug of Celite® filter        agent. The filtered solution was treated with a saturated        solution of sodium bicarbonate, washed with brine, dried over        anhydrous sodium sulfate, filtered and concentrated under        reduced pressure to give 3-bromo-5-chloro-1,2-diaminobenzene as        an off-white solid (0.86 g, 98%). Rf=0.25 (3:7 EA/heptane).

Example 39N-[1-Cyano-1-methyl-2-(4,5,7-trichloro-2H-benzotriazol-2-yl)-ethyl]-4-trifluoromethoxybenzamide(compound No 1.064)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile(150 mg), the title compound was isolated as a white solid (210 mg,87%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=492. 1H NMR: (400 MHz,DMSO-d₆): 1.76 (s, 3H), 5.45 (d, 1H), 5.59 (d, 1H), 7.47 (d, J=8.25 Hz,2H), 7.69 (dd, J=1.5, 0.8 Hz, 1H), 7.81-8.04 (m, 3H) and 8.83 (s, 1H).19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile[1.3 g, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similarto that described in Example 1, part a and b, except starting from4,5,7-trichloro-1H-benzotriazole. 4,5,7-Trichloro-1H-benzotriazole (4 g,85%) was prepared using a procedure similar to that described in Example11, part a, except starting from 2-nitro-3,4,6-trichloroaniline (6.1 g)that was prepared as follows:

-   -   a. 2,4,5-trichloroaniline (10 g) was dissolved in acetic        anhydride (50 mL) and stirred overnight at room temperature. The        resulting solid was filtered and air dried to give        N-(2,4,5-trichlorophenyl)acetamide as an off white solid (12 g,        99%). Rf=0.5 (1:1 EA/heptane).    -   b. To a solution of N-(2,4,5-trichlorophenyl)acetamide (12 g) in        concentrated sulfuric acid (50 mL) at 0° C., was added dropwise,        concentrated nitric acid (8 mL). After addition was complete,        the mixture was allowed to warm slowly to room temperature.        After 5 hours, the mixture was poured into ice water (200 mL).        The resulting solid was filtered, washed with water and        crystallized from a mixture of water and ethanol. The resulting        solid was filtered and dried to give        N-(2-nitro-3,4,6-trichlorophenyl)-acetamide as a grey solid (12        g, 99%).    -   c. A solution of N-(2-nitro-3,4,6-trichlorophenyl)acetamide        (7 g) in dioxane and concentrated hydrochloric acid (70 mL) was        heated at reflux overnight. The mixture was concentrated under        reduced pressure to remove dioxane, diluted with water (150 mL),        neutralized with a saturated solution of sodium bicarbonate and        extracted with ethyl acetate. The organic phase was washed with        brine, dried over anhydrous sodium sulfate, filtered and        concentrated under reduced pressure to give        2-nitro-3,4,6-trichloroaniline as a grey solid (6.1 g,        quantitative). Rf=0.6 (3:7 EA/heptane).

Example 40N-[1-Cyano-1-methyl-2-(4,5,7-trichloro-2H-benzotriazol-2-yl)-ethyl]-4-trifluoromethylthiobenzamide(compound No 1.065)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile(150 mg, described in Example 39) and 4-trifluoromethylthiobenzoylchloride (0.1 mL), the title compound was isolated as a white solid (200mg, 80%). Rf=0.55 (1:1 EA/heptane). MS (ES): M/Z [M+H]=508. NMR: (400MHz, DMSO-d₆): 1.76 (s, 3H), 5.45 (d, J=13.3 Hz, 1H), 5.61 (d, J=13.3Hz, 1H), 7.83-7.92 (m, 4H), 7.94 (s, 1H) and 8.91 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −42.0 (s, 3F).

Example 41N-[1-Cyano-1-methyl-2-(4,5,7-trichloro-2H-benzotriazol-2-yl)-ethyl]-4-(1,2,2,2-tetrafluoroethyl)benzamide(compound No 1.069)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile(35 mg, described in Example 39) and 4-(1,2,2,2-tetrafluoroethyl)benzoylchloride, the title compound was isolated as a solid (6.2 mg, 11%). MS(ES): M/Z [M+H]=508. NMR: (400 MHz, CHLOROFORM-d): 1.90 (s, 3H), 5.20(d, J=13.8 Hz, 1H), 5.53 (d, J=13.8 Hz, 1H), 5.69 (dq, J=44.3 Hz, 5.9Hz, 1H), 7.54 (br.s, 1H), 7.58 (s, 1H), 7.60 (d, J=8.1 Hz, 2H) and 7.98(d, J=8.2 Hz, 2H). 19F NMR (376 MHz, CHLOROFORM-d): −197.6-−197.1 (m,1F), −79.0 (q, J=5.9 Hz, 3F).

4-(1,2,2,2-Tetrafluoroethyl)benzoyl chloride was prepared as follows:

-   -   a. To a solution of 4-formylbenzoic acid methyl ester (4 g) in        THF (40 mL), was added a solution of tetrabutylammonium fluoride        (1 molar in THF, 2.4 mL), followed by a solution of        (trifluoromethyl)trimethylsilane (2 molar THF, 13.4 mL). Water        was added to quench the reaction and the mixture was extracted        with ethyl acetate. The organic phase was dried over anhydrous        sodium sulfate, filtered and the filtrate concentrated under        reduced pressure to give a residue that was purified by        chromatography (SiO₂, heptane/EA) to afford methyl        4-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (4.5 g, 78%). 1H NMR:        (400 MHz, DMSO-d₆): 3.86 (s, 3H), 5.30 (m, 1H), 7.01 (d, J=5.7        Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 8.00 (d, J=8.4 Hz, 2H). 19F NMR        (376 MHz, DMSO-d₆): −77.0 (d, J=7.3 Hz, 3F).    -   b. To a cooled solution of methyl        4-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (0.94 g) in DCM (9        mL) was added of (diethylamino)sulfur trifluoride (1.2 mL). The        mixture was allowed to warm slowly to room temperature        overnight. Water was added and the mixture was extracted with        more DCM. The organic phase was washed with water and brine,        dried over anhydrous sodium sulfate, filtered and the filtrate        concentrated under reduced pressure to afford methyl        4-(1,2,2,2-tetrafluoroethyl)benzoate (0.94 g, 99%). 1H NMR: (400        MHz, DMSO-d₆): 3.88 (s, 3H), 6.52 (m, 1H), 7.69 (d, J=8.2 Hz,        2H), 8.09 (d, J=8.1 Hz, 2H). 19F NMR (376 MHz, DMSO-d₆): −197.9        (m, 1F), −78.0 (m, 3F)    -   c. A mixture of methyl 4-(1,2,2,2-tetrafluoroethyl)benzoate (190        mg) and lithium hydroxide (19 mg) in methanol and water was        stirred at room temperature overnight. The mixture was made        slightly acidic with a solution of 6 normal hydrochloric acid        and then extracted with ethyl acetate. The organic phase was        dried over anhydrous sodium sulfate, filtered and the filtrate        concentrated under reduced pressure to afford        4-(1,2,2,2-tetrafluoroethyl)benzoic acid (86 mg, 48%). 1H NMR:        (400 MHz, DMSO-d₆): 6.50 (m, 1H), 7.65 (d, J=8.2 Hz, 2H), 8.07        (d, J=8.0 Hz, 2H), 13.43 (br. s., 1H). 19F NMR (376 MHz,        DMSO-d₆): −199.0-−196.4 (m, 1F), −78.0 (m, 3F)    -   d. Oxalyl chloride (0.13 mL) was added to        4-(1,2,2,2-tetrafluoroethyl)benzoic acid (96 mg) in DCM (5 mL)        and dimethyl formamide (0.2 mL). After 4 hours at room        temperature, the mixture was concentrated under reduced pressure        to afford 4-(1,2,2,2-tetrafluoroethyl)benzoyl chloride.

Example 42N-[2-(4-Chloro-6-methoxy-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.070)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-chloro-6-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile(50 mg), the title compound was isolated as a white solid (87 mg, 88%).MS (ES): M/Z [M+H]=454. 1H NMR: (400 MHz, DICHLOROMETHANE-d₂): 1.86 (s,3H), 3.88 (s, 3H), 5.11 (d, J=13.9 Hz, 1H), 5.35 (d, J=13.9 Hz, 1H),7.05 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H),7.67 (s, 1H) and 7.93 (d, J=8.8 Hz, 2H). 19F NMR (376 MHz,DICHLOROMETHANE-d₂): −58.5 (s, 3F).

2-amino-3-(4-chloro-6-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrilewas prepared using a procedure similar to that described in Example 1,part a and b, except starting from 7-chloro-5-methoxy-1H-benzotriazole.7-Chloro-5-methoxy-1H-benzotriazole (0.8 g) was prepared using aprocedure similar to that described in Example 13, part a, exceptstarting from 3-chloro-1,2-diamino-5-methoxybenzene.3-Chloro-1,2-diamino-5-methoxybenzene (1.88 g, 75%) was prepared using aprocedure similar to that described in Example 38, part a and b, exceptstarting from 4-methoxy-2-nitroaniline (16.8 g) and N-chlorosuccinimide(15 g) in part a to yield 6-chloro-4-methoxy-2-nitroaniline (2.9 g, 14%)used in part b.

Example 43N-[2-(4-Chloro-6-methoxy-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.071)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-chloro-6-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile(50 mg, described in Example 42) and 4-trifluoromethylthiobenzoylchloride (0.04 mL), the title compound was isolated as a white solid (45mg, 51%). MS (ES): M/Z [M+H]=470. 1H NMR: (400 MHz, DICHLOROMETHANE-d₂):1.86 (s, 3H), 3.88 (s, 3H), 5.11 (d, J=13.9 Hz, 1H), 5.36 (d, J=13.9 Hz,1H), 7.05 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.72 (s, 1H), 7.79(d, J=8.2 Hz, 2H) and 7.92 (d, J=8.6 Hz, 2H). 19F NMR (376 MHz,DICHLOROMETHANE-d₂): −42.8 (s, 3F).

Example 44N-[1-cyano-2-(5-methoxy-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.072)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile (150mg), the title compound was isolated as a white solid (190 mg, 70%).Rf=0.35 (1:1 EA/heptane). MS (ES): M/Z [M+H]=420. 1H NMR: (400 MHz,DMSO-d₆): 1.73 (s, 3H), 3.84 (s, 3H), 5.32 (d, J=13.4 Hz, 1H), 5.37 (d,J=13.4 Hz, 1H), 7.10 (dd, J=9.3, 2.1 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H),7.52 (d, J=8.1 Hz, 2H), 7.82 (dd, J=9.3, 0.4 Hz, 1H), 7.95 (d, J=8.9 Hz,2H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-amino-3-(5-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile wasprepared using a procedure similar to that described in Example 1, parta and b, except starting from 5-methoxy-1H-benzotriazole that wasprepared as follows:

-   -   a. To a solution of 1,2-diamino-4-methoxybenzene hydrochloride        (2 g) in acetonitrile (20 mL) was added dropwise        tert-butylnitrile (1.35 mL) at 0° C. After 4 hours at room        temperature, the mixture was concentrated under reduced pressure        to a solid residue, which was then dissolved in water. The        aqueous solution was neutralized with a saturated solution of        sodium bicarbonate and extracted with ethyl acetate. The organic        phase was washed with brine, dried over anhydrous sodium        sulfate, filtered and the filtrate concentrated under reduced        pressure to afford 5-methoxy-1H-benzotriazole as an off-white        solid (1.2 g, 85%). MS (ES): M/Z [M+H]=150.

Example 45N-[1-cyano-2-(5-methoxy-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.073)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-methoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile (120mg, described in Example 44) and 4-trifluoromethylthiobenzoyl chloride(0.16 mL), the title compound was isolated as a white solid (150 mg,66%). Rf=0.3 (1:1 EA/heptane). MS (ES): M/Z [M+H]=436. 1H NMR: (400 MHz,DMSO-d₆): 1.73 (s, 3H), 3.84 (s, 3H), 5.32 (d, J=13.4 Hz, 1H), 5.38 (d,J=13.4 Hz, 1H), 7.10 (dd, J=9.3, 2.3 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H),7.82 (dd, J=9.2, 0.4 Hz, 1H), 7.87 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.6 Hz,2H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −41.9 (s, 3F).

Example 46N-[1-Cyano-2-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.090)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-2-methylpropionitrile(90 mg), the title compound was isolated as a white solid (65 mg, 44%).Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=476. 1H NMR: (400 MHz,DMSO-d₆): 1.76 (s, 3H), 5.47 (d, J=13.3 Hz, 1H), 5.58 (d, J=13.4 Hz,1H), 7.50 (d, J=8.1 Hz, 2H), 7.70-8.10 (m, 3H) and 8.86 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −127.6 (d, J=5.9 Hz, 1F) and −57.1 (s, 3F).

2-Amino-3-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-2-methylpropionitrile[1.3 g, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similarto that described in Example 1, part a and b, except starting from5,7-dichloro-4-fluoro-1H-benzotriazole.5,7-Dichloro-4-fluoro-1H-benzotriazole (4 g, 85%) was prepared using aprocedure similar to that described in Example 11, part a, exceptstarting from 4,6-dichloro-3-fluoro-2-nitroaniline.4,6-Dichloro-3-fluoro-2-nitroaniline (6.1 g) was prepared using aprocedure similar to that described in Example 39, part a, b and c,except starting from 2,4-dichloro-5-fluoroaniline (10 g).

Example 47N-[1-Cyano-2-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.091)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-2-methylpropionitrile(90 mg, described in Example 46) and 4-trifluoromethylthiobenzoylchloride (0.06 mL), the title compound was isolated as a white solid (95mg, 62%). Rf=0.55 (1:1 EA/heptane). MS (ES): M/Z [M+H]=492. NMR: (400MHz, DMSO-d₆): 1.76 (s, 3H), 5.47 (d, J=13.3 Hz, 1H), 5.60 (d, J=13.3Hz, 1H), 7.58-8.22 (m, 5H) and 8.94 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−127.6 (d, J=5.3 Hz, 1F) and −42.0 (s, 3F).

Example 48N-[2-(5-Chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.092)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(120 mg), the title compound was isolated as a white solid (85 mg, 41%).Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=452. 1H NMR: (400 MHz,DMSO-d₆): 1.74 (s, 3H), 2.43 (s, 3H), 2.45 (s, 3H), 5.35 (d, J=13.3 Hz,1H), 5.52 (d, J=13.3 Hz, 1H), 7.25 (d, J=0.6 Hz, 1H), 7.51 (d, J=8.1 Hz,2H), 7.91 (d, J=8.8 Hz, 2H) and 8.78 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −57.2 (s, 3F).

2-Amino-3-(5-chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile[1.3 g, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similarto that described in Example 1, part a and b, except starting from5-chloro-4,7-dimethyl-1H-benzotriazole.5-Chloro-4,7-dimethyl-1H-benzotriazole (4 g, 85%) was prepared using aprocedure similar to that described in Example 11, part a, exceptstarting from 4-chloro-3,6-dimethyl-2-nitroaniline.4-Chloro-3,6-dimethyl-2-nitroaniline (6.1 g) was prepared using aprocedure similar to that described in Example 39, part a, b and c,except starting from 4-chloro-2,5-dimethylaniline (10 g).

Example 49N-[2-(5-Chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.093)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(120 mg, described in Example 48) and 4-trifluoromethylthiobenzoylchloride (0.09 mL), the title compound was isolated as a white solid(180 mg, 85%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=468. NMR:(400 MHz, DMSO-d₆): 1.74 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 5.34 (d,J=13.3 Hz, 1H), 5.54 (d, J=13.3 Hz, 1H), 7.24 (d, J=0.7 Hz, 1H),7.81-7.93 (m, 4H) and 8.86 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.1(s, 3F).

Example 50N-[2-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.094)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(120 mg), the title compound was isolated as a white solid (130 mg,68%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=500. 1H NMR: (400MHz, DMSO-d₆): 1.75 (s, 3H), 2.42 (s, 3H), 5.40 (d, J=13.3 Hz, 1H), 5.54(d, J=13.4 Hz, 1H), 7.45 (d, J=5.7 Hz, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.91(d, J=8.7 Hz, 2H) and 8.82 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −122.4(d, J=5.3 Hz, 1F) and −57.1 (s, 3F).

2-Amino-3-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile[1.3 g, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similarto that described in Example 1, part a and b, except starting from5-bromo-4-fluoro-7-methyl-1H-benzotriazole.5-Bromo-4-fluoro-7-methyl-1H-benzotriazole (4 g, 85%) was prepared usinga procedure similar to that described in Example 11, part a, exceptstarting from 4-bromo-3-fluoro-6-methyl-2-nitroaniline.4-Bromo-3-fluoro-6-methyl-2-nitroaniline (6.1 g) was prepared using aprocedure similar to that described in Example 39, part a, b and c,except starting from 4-bromo-5-fluoro-2-methylaniline (10 g).

Example 51N-[2-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.095)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(120 mg, described in Example 50) and 4-trifluoromethylthiobenzoylchloride (0.09 mL), the title compound was isolated as a white solid(175 mg, 88%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=516. NMR:(400 MHz, DMSO-d₆): 1.75 (s, 3H), 2.41 (s, 3H), 5.41 (d, J=13.3 Hz, 1H),5.56 (d, J=13.3 Hz, 1H), 7.45 (dd, J=5.9, 1.1 Hz, 1H), 7.85-7.90 (m,4H), 8.90 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −122.4 (d, J=5.3 Hz, 1F),−42.0 (s, 3F).

Example 52N-[2-(4-Bromo-5-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.057)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-bromo-5-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile(48 mg), the title compound was isolated as a white solid (43 mg, 56%).MS (ES): M/Z [M+H]=502. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.42(d, J=13.4 Hz, 1H), 5.54 (d, J=13.4 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H),7.63 (d, J=9.0 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H), 8.02 (d, J=9.0 Hz, 1H)and 8.88 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-amino-3-(4-bromo-5-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile(48 mg) was prepared using a procedure similar to that described inExample 1, part a and b, except starting from4-bromo-5-chloro-1H-benzotriazole (213 mg) that was prepared as follows:

-   -   a. To a solution of 5-chloro-1H-benzotriazole (1 g) and sodium        acetate (1 g) in acetic acid was added bromine (2 g). After 10        days at room temperature, the mixture was treated with a        saturated solution sodium thiosulfate, neutralized with a        saturated solution of sodium bicarbonate and extracted with        ethyl acetate. The organic phase was washed with brine, dried        over anhydrous sodium sulfate, filtered and the filtrate        concentrated under reduced pressure to afford a residue that was        purified by semi-preparative liquid chromatography to afford        4-bromo-5-chloro-1H-benzotriazole as an off-white solid (213 mg,        14%). MS (ES): M/Z [M+H]=232. 1H NMR: (400 MHz, DMSO-d₆): 7.58        (d, J=8.7 Hz, 2H) and 7.91 (d, J=8.7 Hz, 1H).

Example 53N-[2-(5-Chloro-4,7-dibromo-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.083)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-4,7-dibromo-2H-benzotriazol-2-yl)-2-methylpropionitrile(390 mg), the title compound was isolated as a white solid (530 mg,90%). MS (ES): M/Z [M+H]=580. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H),5.43 (d, J=13.3 Hz, 1H), 5.59 (d, J=13.4 Hz, 1H), 7.51 (d, J=8.0 Hz,2H), 7.84-7.96 (m, 2H), 8.04 (s, 1H) and 8.83 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(5-chloro-4,7-dibromo-2H-benzotriazol-2-yl)-2-methylpropionitrile(440 mg) was prepared using a procedure similar to that described inExample 1, part a and b, except starting from5-chloro-4,7-dibromo-1H-benzotriazole (4.2 g) that was prepared asfollows by adapting a procedure described in the literature by K.Kopańska et al. in Bioorganic & Medicinal Chemistry, volume 13 (2005)page 3601 and in Bioorganic & Medicinal Chemistry, volume 12 (2004),pages 2617-2624:

-   -   a. To a solution of 5-chloro-1H-benzotriazole (7.7 g) and silver        sulfate (19 g) in sulfuric acid (100 mL) was slowly added        bromine (15 mL). After 2 days at room temperature, water was        slowly added to the chilled mixture and the mixture stirred at        room temperature for 3 days. The resulting solid was filtered,        washed with water and triturated with ethyl acetate. The organic        filtrate was collected and treated with a saturated solution of        sodium bisulfite, a saturated solution of sodium bicarbonate,        then water, dried over anhydrous sodium sulfate and filtered        through a pad of Celite®. The filtrate was concentrated under        reduced pressure to afford 5-chloro-4,7-dibromo-1H-benzotriazole        as a solid (11.2 g, 71%). MS (ES): M/Z [M+H]=310. 1H NMR: (400        MHz, DMSO-d6): 8.0 (s, 1H).

Example 54N-[2-(5-Chloro-4,7-dibromo-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.085)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-4,7-dibromo-2H-benzotriazol-2-yl)-2-methylpropionitrile(44 mg, described in Example 53) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (15 mg, 22%).MS (ES): M/Z [M−H]=594. NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.43 (d,J=13.4 Hz, 1H), 5.61 (d, J=13.3 Hz, 1H), 7.88 (q, J=8.5 Hz, 4H), 8.04(s, 1H) and 8.91 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.0 (s, 3F).

Example 55N-[2-(4-Bromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.086)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-bromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile,the title compound was isolated as a white solid (260 mg). MS (ES): M/Z[M+H]=536. 1H NMR: (400 MHz, DMSO-d₆): 1.76 (s, 3H), 5.44 (d, J=13.2 Hz,1H), 5.59 (d, J=13.4 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.84-7.99 (m, 3H)and 8.83 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(4-bromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrilewas prepared using a procedure similar to that described in Example 1,part a and b, except starting from 4-bromo-5,7-dichloro-1H-benzotriazolethat was prepared along with 4,6-dibromo-5,7-dichloro-1H-benzotriazoleusing a procedure similar to that described in Example 53 except using5,7-dichloro-1H-benzotriazole described in Example 15.

Example 56N-[2-(4-Bromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.087)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4-bromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrileand 4-trifluoromethylthiobenzoyl chloride, the title compound wasisolated as a white solid (110 mg, described in Example 55). MS (ES):M/Z [M+H]=552. NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.44 (d, J=13.3Hz, 1H), 5.60 (d, J=13.7 Hz, 1H), 7.75-8.04 (m, 5H) and 8.91 (s, 1H).19F NMR (376 MHz, DMSO-d₆): −42.0 (s, 3F).

Example 57N-[1-Cyano-2-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.088)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile,the title compound was isolated as a white solid (130 mg). MS (ES): M/Z[M+H]=614. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.45 (d, J=13.3 Hz,1H), 5.59 (d, J=13.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.91 (d, J=8.8 Hz,2H) and 8.82 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrilewas prepared using a procedure similar to that described in Example 1,part a and b, except starting from4,6-dibromo-5,7-dichloro-1H-benzotriazole that was prepared along with4-bromo-5,7-dichloro-1H-benzotriazole described in Example 55 using aprocedure similar to that described in Example 53 except using5,7-dichloro-1H-benzotriazole described in Example 15.

Example 58N-[1-Cyano-2-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.089)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile,described in Example 57, and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (100 mg). MS (ES): M/Z[M+H]=630. NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.45 (d, J=13.3 Hz,1H), 5.60 (d, J=13.0 Hz, 1H), 7.82-7.92 (m, 4H) and 8.90 (s, 1H). 19FNMR (376 MHz, DMSO-d₆): −42.0 (s, 3F).

Compounds of Examples 59 and 60 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—H; W=C—Cl; X=C—H; Y=C—CH═CH₂;Q=P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 59N-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.075)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-vinyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(2.3 g), the title compound was isolated as a white solid (3.2 g, 80%).Rf=0.45 (1:1 EA/heptane). MS (ES): M/Z [M+H]=450. 1H NMR: (400 MHz,DMSO-d₆): 1.75 (s, 3H), 5.41 (d, J=13.3 Hz, 1H), 5.51 (dd, J=11.2, 1.2Hz, 1H), 5.55 (d, J=13.4 Hz, 1H), 6.45 (dd, J=17.7, 1.2 Hz, 1H), 6.91(dd, J=17.6, 11.3 Hz, 1H), 7.48-7.52 (m, 3H), 7.93 (d, J=8.8 Hz, 2H),8.03 (d, J=1.8 Hz, 1H), and 8.87 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−57.1 (s, 3F).

2-Amino-3-(6-chloro-4-vinyl-2H-benzotriazol-2-yl)-2-methylpropionitrile[2.3 g, 97%, Rf=0.3 (1:1 EA/heptane)] was prepared using a proceduresimilar to that described in Example 1, part b, except starting from1-(6-chloro-4-vinyl-2H-benzotriazol-2-yl)-propan-2-one.1-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-propan-2-one (4 g, 85%) wasprepared as follows:

-   -   a. 1-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-propan-2-one (3 g),        tributylvinyltin (3.5 g) and bis(tri-t-butylphosphine)palladium        (0.5 g) were heated in toluene (20 mL) at 50° C. overnight. The        mixture was concentrated under reduced pressure, taken up in        ethyl acetate and filtered through a plug of Celite®. Filtrate        was concentrated under reduced pressure to give a residue that        was purified by chromatography (SiO₂, heptane/EA) to afford        1-(6-chloro-4-vinyl-2H-benzotriazol-2-yl)-propan-2-one as a        white solid (2.2 g, 90%). Rf=0.5 (1:1 EA/heptane).        1-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-propan-2-one was        prepared using a procedure similar to that described in Example        1, part a, except starting from        7-bromo-5-chloro-1H-benzotriazole described in Example 38, part        a and b.

Example 60N-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.076)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-4-vinyl-2H-benzotriazol-2-yl)-2-methylpropionitrile(50 mg) described in Example 59 above and 4-trifluoromethylthiobenzoylchloride (0.05 mL), the title compound was isolated as a white solid (65mg, 73%). Rf=0.5 (1:1 EA/heptane). MS (ES): M/Z [M+H]=466. NMR: (400MHz, DMSO-d₆): 1.75 (s, 3H), 5.41 (d, J=13.4 Hz, 1H), 5.50 (d, J=11.5Hz, 1H), 5.57 (d, J=13.4 Hz, 1H), 6.45 (d, J=17.6 Hz, 1H), 6.91 (dd,J=17.6, 11.3 Hz, 1H), 7.51 (s, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.91 (d,J=8.3 Hz, 2H), 8.03 (s, 1H) and 8.96 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −42.0 (s, 3F).

Compounds of Examples 61 to 67 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—H; W=C—Cl; X=C—H; Y=C—R₁₁;R₁₁=CO₂H, CO₂Me, CH₂N(CH₃)₂, CH₂OH, CH(OH)CH₂OH, CHFCH₂FQ=P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-OCF₃

Example 61N-{2-[6-Chloro-4-(1,2-dihydroxyethyl)-2H-benzotriazol-2-yl]-1-cyano-1-methyl-ethyl}-4-trifluoromethoxybenzamide(compound No 1.077)

To a solution ofN-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(0.25 g) in 5 mL of a mixture of THF and water (10 to 1), was addedsodium periodate (0.24 g, 2.1 equivalent) and a 4% osmium tetroxidesolution in water (17 mL, 5 mole %). After 2 hours at room temperature,the mixture was quenched with a 10% solution of sodium thiosulfate,extracted with ethylacetate and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure to give a residue that was purified by chromatography (SiO₂,heptane/EA) to afford the title compound as a white solid mixture ofdiastereoisomers (110 mg, 40%). Rf=0.35 (1:1 EA/heptane). MS (ES): M/Z[M+H]=484. 1H NMR: (400 MHz, DMSO-d₆): 1.74-1.75 (d, 3H), 3.40-3.56 (m,1H), 3.67-3.82 (m, 1H), 4.78 (dt, J=17.3, 6.0 Hz, 1H), 5.01-5.12 (m,1H), 5.35-5.43 (m, 1H), 5.43-5.51 (m, 1H), 5.61 (d, J=4.8 Hz, 1H), 7.42(s, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.93 (dd, J=8.7, 3.8 Hz, 2H), 7.98 (t,J=2.1 Hz, 1H) and 8.92 (d, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s,3F).

Example 62N-{2-[6-Chloro-4-(1,2-difluoroethyl)-2H-benzotriazol-2-yl]-1-cyano-1-methyl-ethyl}-4-trifluoromethoxybenzamide(compound No 1.078)

To a solution ofN-{2-[6-Chloro-4-(1,2-dihydroxyethyl)-2H-benzotriazol-2-yl]-1-cyano-1-methyl-ethyl}-4-trifluoromethoxybenzamide(50 mg) in DCM (3 mL), was added Deoxofluor™[Bis(2-methoxyethyl)aminosulfur Trifluoride] (0.07 mL). After stirringovernight at room temperature, the mixture was concentrated underreduced pressure to give a residue that was purified by chromatography(SiO₂, heptane/EA) to afford the title compound as a white solid mixtureof diastereoisomers (35 mg, 69%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z[M+H]=488. 1H NMR: (400 MHz, CHLOROFORM-d): 1.88-1.89 (d, 3H), 4.71-5.00(m, 2H), 5.19 (dd, J=13.7, 4.5 Hz, 1H), 5.47 (t, J=13.9 Hz, 1H),5.99-6.25 (m, 1H), 7.20 (d, J=18.7 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.53(s, 1H), 7.86 (d, J=8.7 Hz, 2H) and 7.90 (s, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −192.2 (s, 1F), −58.1 (s, 3F) and 3.1 (br. s., 1F).

Example 63N-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.079)

A solution ofN-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(0.29 g) in 35 mL of a 3 to 1 mixture of DCM and methanol was treatedwith ozone gas for 15 minutes. After stirring one hour at −78° C., themixture was purged 10 minutes with oxygen and then quenched withdimethyl sulfide followed by a 10% solution of sodium thiosulfate, thendiluted with DCM (100 mL). The mixture was separated, and the organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure to give a residue that was purified by chromatography(SiO₂, heptane/EA) to afford the title compound as a white solid (0.23g, 79%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=452. 1H NMR: (400MHz, CHLOROFORM-d): 1.58 (s, 3H), 5.24 (d, J=13.8 Hz, 1H), 5.47 (d,J=13.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.94 (br. s, 1H), 8.00 (d, J=1.8Hz, 1H), 8.05 (m, 2H), 8.22 (d, J=1.9 Hz, 1H) and 10.34 (s, 1H). 19F NMR(376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

Example 64N-[2-(6-Chloro-4-dimethylaminomethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.080)

To a solution ofN-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(0.18 g) in methanol (3 mL) was added a 2 molar methanolic solution ofdimethylamine (0.24 mL). After one hour stirring at room temperature,decaborane was added (15 mg) and the mixture stirred one more hourbefore being concentrated under reduced pressure. The residue waspurified by chromatography (SiO₂, heptane/EA) to afford the titlecompound as a white solid (100 mg, 52%). Rf=0.2 (3:1 EA/heptane). MS(ES): M/Z [M+H]=481. 1H NMR: (400 MHz, CHLOROFORM-d): 1.81 (s, 3H), 2.31(s, 6H), 3.75 (d, J=13.5 Hz, 1H), 3.92 (d, J=13.5 Hz, 1H), 5.12 (d,J=13.8 Hz, 1H), 5.52 (d, J=13.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.36(s, 1H), 7.81 (d, J=1.7 Hz, 1H) and 7.95 (br. d, J=8.7 Hz, 3H). 19F NMR(376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

Example 65N-[2-(6-Chloro-4-hydroxymethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.081)

To a solution ofN-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(150 mg) in ethanol (2 mL) cooled in an ice bath was added sodiumtriacetoxyborohydride (0.22 g). After 6 hour at room temperature, moresodium triacetoxyborohydride (0.29 g) was added and the mixture stirredovernight at room temperature. The mixture was quenched with water,extracted with ethyl acetate. The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue that was purified by chromatography (SiO₂, heptane/EA) to affordthe title compound as a white solid (100 mg, 67%). Rf=0.4 (3:1EA/heptane). MS (ES): M/Z [M+H]=454. 1H NMR: (400 MHz, CHLOROFORM-d):1.87 (s, 3H), 5.06 (s, 2H), 5.15 (d, J=13.8 Hz, 1H), 5.43 (d, J=13.8 Hz,1H), 7.33 (d, J=8.8 Hz, 2H), 7.43 (dt, J=1.8, 1.0 Hz, 1H), 7.47 (s, 1H),7.80 (d, J=1.8 Hz, 1H) and 7.88 (d, J=8.8 Hz, 2H). 19F NMR (376 MHz,CHLOROFORM-d): −58.1 (s, 3F).

Example 666-Chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}amino)-propyl]-2H-benzotriazole-4-carboxylicacid (compound No 1.082)

To a solution ofN-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(1.5 g) in a mixture of THF (25 mL), t-butanol (10 mL) and2-methyl-2-butene was added dropwise the solution of sodium hypochlorite(0.9 g) and sodium dihydrogen phosphate (1.15 g) in water (20 mL). After4 hour at room temperature, the mixture was concentrated under reducedpressure, diluted with water (50 mL) and acidified to pH 2 with normalHCl. The white solid was filtered and washed with water and dried undervacuum to give the title compound (1.35 g, 87%). MS (ES): M/Z [M+H]=468.1H NMR: (400 MHz, DMSO-d₆): 1.72 (s, 3H), 5.48-5.64 (m, 2H), 7.43 (d,J=8.2 Hz, 2H), 7.83 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.23 (d,J=1.8 Hz, 0H) and 9.41 (br. s., 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1(s, 3F).

Example 67 Methyl6-chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}-amino)propyl]-2H-benzotriazole-4-carboxylate(compound No 1.084)

A 2 molar ether solution of trimethylsilyldiazomethane was added to6-chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}amino)-propyl]-2H-benzotriazole-4-carboxylicacid (100 mg) dissolved in a ten to 1 one mixture of THF and methanol (2mL). After overnight at room temperature, the mixture was concentratedunder reduced pressure to give a residue that was purified bychromatography (SiO₂, heptane/EA) to afford the title compound as awhite solid (42 mg, 40%). MS (ES): M/Z [M+H]=482. 1H NMR: (400 MHz,DMSO-d₆): 1.75 (s, 3H), 3.78 (s, 3H), 5.44 (d, J=13.3 Hz, 1H), 5.58 (d,J=13.3 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H), 8.02 (d,J=1.9 Hz, 1H), 8.52 (d, J=1.9 Hz, 1H) and 8.87 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −57.1 (s, 3F).

The preparation of6-chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}amino)-propyl]-2H-benzotriazole-4-carboxylicacid is described in Example 66 above.

Compound of Example 68 was Prepared According to the Following ReactionScheme

Final ProductV=C—H; W=C—Cl; X=C—H; Y=C—CH₂NH₂;Q=P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 68N-[2-(4-Aminomethyl-6-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.074)

To a solution of{6-chloro-2-[2-cyano-2-methyl-2-(4-trifluoromethoxy-benzoylamino)-ethyl]-2H-benzotriazol-4-ylmethyl}-carbamicacid tert-butyl ester (100 mg) in DCM (2 mL) was added trimethylsilyliodide (0.05 mL). After 20 minutes, the mixture was quenched withmethanol and concentrated under reduced pressure. The residue was takenup in ethyl acetate, washed with a saturated solution of sodiumbicarbonate, dried over sodium sulfate, filtered and concentrated underreduced pressure to give the title compound as a white solid (70 mg,87%). Rf=0.2 (1:1 EA/heptane). MS (ES): M/Z [M+H]=453. 1H NMR: (500 MHz,CHLOROFORM-d): 1.86 (s, 3H), 4.21 (d, J=3.4 Hz, 2H), 5.16 (d, J=13.7 Hz,1H), 5.43 (d, J=13.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.33 (d, J=0.7 Hz,1H), 7.60 (s, 1H), 7.75 (d, J=1.5 Hz, 1H) and 7.88 (d, J=8.7 Hz, 2H).19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

The starting material{6-chloro-2-[2-cyano-2-methyl-2-(4-trifluoromethoxy-benzoylamino)-ethyl]-2H-benzotriazol-4-ylmethyl}-carbamicacid tert-butyl ester [0.25 g, 60%, MS (ES): M/Z [M+H]=553)] wasprepared using a procedure similar to that described in Example 1 exceptstarting from[2-(2-amino-2-cyano-2-methylethyl)-6-chloro-2H-benzotriazol-4-ylmethyl]-carbamicacid tert-butyl ester (0.28 g) that was prepared using a proceduresimilar to that described in Example 1, part b, except starting from[6-chloro-2-(2-oxopropyl)-2H-benzotriazol-4-ylmethyl]-carbamic acidtert-butyl ester (0.4 g) that was prepared as follows:

-   -   a. 1-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-propan-2-one (3.5        g), zinc cyanide (2.8 g), zinc powder (0.4 g) and        bis(tri-t-butylphosphine)palladium (0.62 g) were heated in        degassed dimethylacetamide (60 mL) at 60° C. After stirring two        hours, the mixture was diluted with water. A solid residue        formed and was filtered, washed with water and taken up in ethyl        acetate. Organic layer was filtered and concentrated under        reduced pressure to give a residue that was purified by        chromatography (SiO₂, heptane/EA) to afford        6-chloro-2-(2-oxopropyl)-2H-benzotriazole-4-carbonitrile as a        white solid (2 g, 70%). Rf=0.55 (1:1 EA/heptane).        1-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-propan-2-one was        prepared using a procedure similar to that described in Example        1, part a, except starting from        7-bromo-5-chloro-1H-benzotriazole described in Example 38, part        a and b.    -   b. To a solution of        6-chloro-2-(2-oxopropyl)-2H-benzotriazole-4-carbonitrile in        methanol (160 mL) at 0° C. was added di-tert-butyl dicarbonate        (7.6 g) and nickel chloride hexahydrate (0.4 g) followed by slow        addition over 1.5 hours of sodium borohydride (5.2). After        stirring one additional hour, the mixture was treated with        diethylenetriamine (1.8 mL), concentrated under reduced        pressure, taken up in ethyl acetate and washed with a saturated        solution of sodium bicarbonate. The organic layer was dried over        sodium sulfate, filtered and concentrated under reduced pressure        to give a brown residue (5.6 g) that contained        [6-chloro-2-(2-hydroxypropyl)-2H-benzotriazol-4-ylmethyl]-carbamic        acid tert-butyl ester and the des-halogeno analog        [2-(2-hydroxypropyl)-2H-benzotriazol-4-ylmethyl]-carbamic acid        tert-butyl ester. This residue was taken directly to the next        step without further purification.    -   c. To a solution of oxalyl chloride (0.8 mL) in DCM (20 mL) was        added dropwise at −78° C. under nitrogen a solution of DMSO (1.2        mL) in DCM (10 mL). After stirring 10 minutes, a solution of the        crude residue containing        6-chloro-2-(2-hydroxypropyl)-2H-benzotriazol-4-ylmethyl]-carbamic        acid tert-butyl ester (1.45 g) in DCM (5 mL) was added dropwise        under nitrogen. After stirring 30 minutes, TEA (5 mL) was added        under nitrogen and the mixture allowed warming to room        temperature. The mixture was concentrated under reduced pressure        to give a residue that was purified by chromatography (SiO₂,        heptane/EA) to afford        [6-chloro-2-(2-oxopropyl)-2H-benzotriazol-4-ylmethyl]-carbamic        acid tert-butyl ester as a yellow solid (0.4 g, 30%). Rf=0.45        (1:1 EA/heptane). 1H NMR: (400 MHz, CHLOROFORM-d): 1.47 (s, 9H),        2.19 (s, 3H), 4.71 (d, J=5.3 Hz, 2H), 5.21 (br. s., 1H), 5.50        (s, 2H), 7.30 (d, J=0.8 Hz, 1H) and 7.78 (d, J=1.3 Hz, 1H).

Compounds of Examples 69 to 74 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—H; W=C—R₉; X=C—H; Y=C—R₁₁;Q=P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 69N-[1-Cyano-2-(4-cyano-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.054)

N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(100 mg, described in Example 19), zinc cyanide (50 mg), zinc powder (10mg), 2-di-t-butylphosphino-1,1′-binaphthyl (40 mg) and palladiumtrifluoroacetate (34 mg) were heated under nitrogen in degasseddimethylacetamide (1 mL) at 100° C. overnight. The mixture wasconcentrated under reduced pressure to give a residue that was purifiedby chromatography (SiO₂, heptane/EA) to afford the title compound as awhite solid (62 mg, 63%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z[M+H]=483. NMR: (400 MHz, DMSO-d₆): 1.77 (s, 3H), 5.56 (d, J=13.3 Hz,1H), 5.66 (d, J=13.3 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.6 Hz,2H), 8.59 (s, 1H), 8.90 (s, 1H) and 9.02 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −61.0 (s, 3F) and −57.1 (s, 3F).

Example 70N-[1-Cyano-2-(4-cyano-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.055)

Using a procedure similar to that described in Example 69, except usingN-[2-(4-chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(100 mg, described in Example 20), the title compound was isolated as awhite solid (52 mg, 53%). Rf=0.5 (1:1 EA/heptane). MS (ES): M/Z[M+H]=499. NMR: (400 MHz, DMSO-d₆): 1.77 (s, 3H), 5.57 (d, J=13.2 Hz,1H), 5.67 (d, J=13.3 Hz, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.4 Hz,2H), 8.60 (d, J=1.1 Hz, 1H), 8.99 (s, 1H) and 9.01 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −42.0 (s, 3F) and −61.0 (s, 3F).

Example 71N-[1-Cyano-2-(6-cyano-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.056)

Using a procedure similar to that described in Example 69, except usingN-[2-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(100 mg, described in Example 32), the title compound was isolated as awhite solid (44 mg, 45%). Rf=0.55 (1:1 EA/heptane). MS (ES): M/Z[M+H]=483. NMR: (400 MHz, DMSO-d₆): 1.78 (s, 3H), 5.53 (d, J=13.2 Hz,1H), 5.68 (d, J=13.3 Hz, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.8 Hz,2H), 8.32 (s, 1H), 8.85 (s, 1H) and 9.18 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −61.7 (s, 3F) and −57.2 (s, 3F).

Example 72N-[1-Cyano-2-(6-cyano-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 1.066)

Using a procedure similar to that described in Example 69, except usingN-[2-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(590 mg, described in Example 33), the title compound was isolated as awhite solid (320 mg, 55%). Rf=0.5 (1:1 EA/heptane). MS (ES): M/Z[M+H]=499. NMR: (400 MHz, DMSO-d₆): 1.78 (s, 3H), 5.53 (d, J=13.2 Hz,1H), 5.69 (d, J=13.3 Hz, 1H), 7.79-7.91 (m, 4H), 8.31 (s, 1H), 8.94 (s,1H) and 9.18 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.1 (s, 3F) and−61.7 (s, 3F).

Example 73N-[2-(6-Chloro-4-cyano-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 1.067)

Using a procedure similar to that described in Example 69, except usingN-[2-(4-bromo-6-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(100 mg) described in Example 38 and bis(tri-t-butylphosphine)palladium(20 mg) as palladium catalyst with no additional phosphine ligand andheating the reaction mixture at 60° C. for one hour; the title compoundwas isolated as a white solid (70 mg, 79%). Rf=0.6 (1:1 EA/heptane). MS(ES): M/Z [M+H]=449. NMR: (400 MHz, DICHLOROMETHANE-d₂): 1.87 (s, 3H),5.28 (d, J=13.7 Hz, 1H), 5.52 (d, J=13.7 Hz, 1H), 7.29-7.43 (m, 3H),7.85 (d, J=1.8 Hz, 1H), 7.87-7.95 (m, 2H) and 8.20 (d, J=1.7 Hz, 1H).19F NMR (376 MHz, DICHLOROMETHANE-d₂): −58.5 (s, 3F).

Example 74N-{2-[6-Chloro-4-(4-trifluoromethylphenyl)-2H-benzotriazol-2-yl]-1-cyano-1-methylethyl}-4-trifluoromethoxybenzamide(compound No 1.068)

N-[2-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(120 mg) described in Example 38, bis(tri-t-butylphosphine)palladium (20mg), bis(dibenzylideneacetone)palladium (20 mg), potassium fluoride (42mg) and 4-trifluoromethylphenyl boronic acid (45 mg) in THF were stirredat room temperature for 3 days. The mixture was concentrated underreduced pressure to give a residue that was purified by chromatography(SiO₂, heptane/EA) to afford a one to one mixture of title compound andstarting material [110 mg, Rf=0.3 (3:7 EA/heptane)]. This mixture wasfurther purified by semi-preparative liquid chromatography(methanol/water) to afford the title compound as pure solid (35 mg,26%). MS (ES): M/Z [M+H]=568. NMR: (400 MHz, DMSO-d₆): 1.74 (s, 3H),1.84 (s, 1H), 5.39 (d, J=13.3 Hz, 1H), 5.64 (d, J=13.3 Hz, 1H), 7.41 (d,J=8.0 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.84 (d, J=1.8 Hz, 1H), 7.93 (d,J=8.9 Hz, 2H), 8.12 (d, J=8.1 Hz, 2H) and 8.23 (d, J=1.8 Hz, 1H). 19FNMR (376 MHz, DMSO-d₆): −61.8 (s, 3F) and −57.3 (s, 3F).

Compounds of Examples 75 to 84 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—R₈; W=C—R₉; X=C—R₁₀; Y=C—R₁₁;Q=P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R; R=S(O)_(n)CF₃; n=0, 1, or 2

Example 75N-[1-Cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylsulfinylbenzamide(compound No 1.022)

3-Chloroperbenzoic acid (77% pure, 0.13 g) was added at 0° C. to a DCMsolution ofN-[1-cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(0.11 g, described in Example 22). The reaction mixture was stirred 72hours at room temperature. The reaction mixture was diluted with DCMthen washed with saturated aqueous sodium bicarbonate solution. Theorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue that was purifiedby chromatography (SiO₂, heptane/EA) to afford the title compound as awhite solid (60 mg, 53%). MS (ES): M/Z [M+H]=447. 1H NMR: (400 MHz,DMSO-d₆): 1.77 (s, 3H), 5.44-5.65 (m, 2H), 7.76 (d, J=8.8 Hz, 1H),8.02-8.07 (m, 4H), 7.94 (d, J=8.9 Hz, 1H), 8.78 (s, 1H) and 9.10 (s,1H). 19F NMR (376 MHz, DMSO-d₆): −74.20 (s, 3F).

Example 76N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfinylbenzamide(compound No 1.023)

Using a procedure similar to that described in Example 75, except usingN-[1-cyano-1-methyl-2-(4-chloro-6-trifluoromethylbenzotriazol-2-yl)-ethyl]-4-trifluoromethylthiobenzamidedescribed in Example 20, the title compound was isolated as a whitesolid (60 mg, 53%). MS (ES): M/Z [M+H]=524. 1H NMR: (400 MHz, DMSO-d₆):1.78 (s, 3H), 5.46-5.56 (m, 2H), 7.94 (d, 1H, J=0.7 Hz), 8.01-8.07 (m,4H), 8.56 (d, J=0.8 Hz, 1H) and 9.02 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −74.27 (s, 3F) and −61.08 (s, 3F).

Example 77N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylsulfinylbenzamide(compound No 1.024)

3-Chloroperbenzoic acid (77% pure, 0.57 g) was added at 0° C. to a DCMsolution ofN-[1-cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(0.3 g, described in Example 16). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM,washed with saturated aqueous sodium bicarbonate solution. The organicphase was dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give a residue that was purified bychromatography (SiO₂, heptane/EA) to afford the title compound as awhite solid (100 mg, 32%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z[M+H]=490. NMR: (400 MHz, DMSO-d₆): 1.76 (s, 3H), 5.39-5.60 (m, 2H),7.74 (d, J=1.6 Hz, 1H), 7.99-8.08 (m, 4H), 8.18 (dd, J=1.5, 0.9 Hz, 1H),and 9.04 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −74.24 (s, 3F).

Example 78N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylsulfonylbenzamide(compound No 1.025)

The crude residue described in Experimental 77 that was purified bychromatography (SiO₂, heptane/EA) also provided the sulfone titlecompound as a white solid (100 mg, 31%). Rf=0.65 (1:1 EA/heptane). MS(ES): M/Z [M+H]=506. NMR: (400 MHz, DMSO-d₆): 1.76 (s, 3H), 5.51 (dd,J=60.1, 13.4 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 8.12-8.17 (m, 2H), 8.19(d, J=1.6 Hz, 1H), 8.31 (d, J=8.4 Hz, 2H) and 9.19 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −78.70 (s, 3F).

Example 79N-[1-Cyano-1-methyl-2-(5-trifluoromethyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylsulfonylbenzamide(compound No 1.026)

3-Chloroperbenzoic acid (60 mg) was added at 0° C. to a DCM solution ofN-[1-cyano-1-methyl-2-(5-trifluoromethyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide(50 mg, described in Example 11). The reaction mixture was stirred 48hours at room temperature then more 3-chloroperbenzoic acid (60 mg) wasadded and the reaction mixture was stirred 48 additional hours at roomtemperature. The reaction mixture was diluted with DCM, washed withsaturated aqueous sodium bicarbonate solution. The organic phase wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give a residue that was purified by chromatography(SiO₂, heptane/EA) to afford the title compound as a white solid (42 mg,79%). Rf=0.5 (1:1 EA/heptane). MS (ES): M/Z [M+H]=506. 1H NMR: (400 MHz,CHLOROFORM-d): 1.90 (s, 3H), 5.40 (dd, J=120.3, 13.8 Hz, 2H), 7.38 (brs, 1H), 7.66 (dd, J=9.1, 1.5 Hz, 1H), 8.07-8.14 (m, 2H), 8.16-8.23 (m,2H) and 8.26 (br s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −78.33 (s, 3F)and −63.04 (s, 3F).

Example 80N-[1-Cyano-1-methyl-2-(5-cyano-2H-benzotriazol-2-yl)-ethyl]-4-trifluoromethylsulfonylbenzamide(compound No 1.027)

Using a procedure similar to that described in Example 79, except usingN-[1-cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(50 mg, described in Example 22), the title compound was isolated as awhite solid (35 mg, 65%). Rf=0.4 (1:1 EA/heptane). MS (ES): M/Z[M+H]=463. 1H NMR: (400 MHz, DMSO-d₆): 1.76 (s, 3H), 5.44-5.65 (m, 2H),7.77 (d, J=8.8 Hz, 1H), 8.15 (d, J=8.6 Hz, 2H), 8.19 (d, J=8.8 Hz, 1H),8.32 (d, J=8.4 Hz, 2H), 8.79 (s, 1H) and 9.26 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −78.67 (s, 3F).

Example 81N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfonylbenzamide(compound No 1.028)

Using a procedure similar to that described in Example 77, except usingN-[2-(4-chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(50 mg, described in Example 20) and a 6 fold excess of3-chloroperbenzoic acid (77% pure, 130 mg), the title compound wasisolated as a white solid (35 mg, 66%). Rf=0.65 (1:1 EA/heptane). MS(ES): M/Z [M+H]=540. 1H NMR: (400 MHz, DMSO-d₆): 1.78 (s, 3H), 5.59 (dd,J=58.3, 13.3 Hz, 2H), 7.93 (s, 1H), 8.16 (d, J=8.58 Hz, 2H), 8.57 (s,1H) and 9.17 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −78.73 (s, 3F) and−61.08 (s, 3F).

Example 82N-[2-(2H-Benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfonylbenzamide(compound No 1.029)

Sodium periodate (200 mg) and ruthenium chloride (10 mg) were added to asolution ofN-[2-(2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(100 mg, described in Example 6), in a mixture of acetonitrile-water(2:1). The reaction mixture was stirred 48 hours whereupon the mixturewas diluted with ethyl acetate and washed with saturated aqueous sodiumbicarbonate solution. The organic filtrate was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure togive to give a residue that was purified by chromatography (SiO₂,heptane/EA) to afford the title compound as a white solid (50 mg, 46%).Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=438. 1H NMR: (400 MHz,DMSO-d₆): 1.75 (s, 3H), 5.39-5.53 (m, 2H), 7.47 (dd, J=6.6, 3.1 Hz, 2H),7.95 (dd, J=6.6, 3.1 Hz, 2H), 8.17 (d, J=8.6 Hz, 2H), 8.31 (d, J=8.4 Hz,2H) and 9.25 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −78.66 (s, 3F).

Example 83N-[1-Cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylsulfonylbenzamide(compound No 1.030)

Using a procedure similar to that described in Example 79, except usingN-[1-cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide(50 mg, described in Example 8), the title compound was isolated as awhite solid (40 mg, 37%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z[M+H]=452. 1H NMR: (400 MHz, DMSO-d₆): 1.73 (s, 3H), 5.34-5.47 (m, 2H),7.30 (dd, J=8.8, 1.4 Hz, 1H), 7.69 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 8.17(d, J=8.5 Hz, 2H), 8.32 (d, J=8.4 Hz, 2H) and 9.24 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −78.67 (s, 3F).

Example 84N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfonylbenzamide(compound No 1.031)

Using a procedure similar to that described in Example 79, except usingN-[2-(5-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(50 mg, described in Example 3), the title compound was isolated as awhite solid (120 mg, 45%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z[M+H]=472. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 5.41-5.52 (m, 2H),7.49 (m, 1H), 8.02 (m, 1H), 8.14-8.32 (m, 4H) and 9.25 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −78.67 (s, 3F).

Compounds of Examples 85 to 88 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—H; W=C—Cl; X=C—H; Y=C—H;Q=P=N;R₃=R₄=H; a=1; R₆=H;Z=C(O); R₇=p-phenyl-R; R=OCF₃ or SCF₃

Example 85N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyanopropyl}-4-trifluoromethoxybenzamide(compound No 1.047)

Using a procedure similar to that described in Example 1, except using2-amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]butyronitrile, thetitle compound was isolated as a solid. MS (ES): M/Z [M+H]=438. 1H NMR:(400 MHz, CHLOROFORM-d): 1.29 (t, J=7.4 Hz, 3H), 1.72-1.94 (m, J=14.4,7.4 Hz, 1H), 2.29 (m, J=14.3, 7.4 Hz, 1H), 5.23 (d, J=13.9 Hz, 1H), 5.47(d, J=13.8 Hz, 1H), 7.15 (s, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.40 (dd,J=9.1, 1.8 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H) and7.87 (d, J=1.2 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]butyronitrile wasprepared using a procedure similar to that described in Example 1, partb, except starting from 1-(5-chloro-2H-benzotriazol-2-yl)butan-2-onethat was prepared as follows:

-   -   a. A solution of 5-chloro-1H-benzotriazole (1.53 g) in THF was        added at 0° C. to a mixture of diisopropylic azodicarboxylate (2        mL), triphenyl phosphine (2.9 g) and allyl alcohol (1.4 mL) in        THF. After stirring one hour at 0° C., the mixture was        concentrated under reduced pressure to give a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        2-allyl-5-chloro-2H-benzotriazole (1.02 g, 53%). A mixture of        1-allyl-5-chloro-1H-benzotriazole and        1-allyl-6-chloro-1H-benzotriazole was also recovered (0.9 g,        47%). Alternatively, 2-allyl-5-chloro-2H-benzotriazole [4.87 g,        25%, Rf=0.4 (1:3 EA/heptane)] was obtained using a procedure        similar to that described in Example 1, part a, except using        3-bromopropene. Similarly, a mixture of        1-allyl-5-chloro-1H-benzotriazole and        1-allyl-6-chloro-1H-benzotriazole was also recovered [10.81 g,        56%, Rf=0.2 (1:3 EA/heptane)].    -   b. 2-Allyl-5-chloro-2H-benzotriazole dissolved in a mixture of        DCM and methanol was treated with ozone gas for 30 minutes.        After stirring one hour at −78° C., the mixture was purged 10        minutes with oxygen and then quenched with dimethyl sulfide        followed by a 10% solution of sodium thiosulfate and diluted        with DCM (100 mL). The organic layer was dried over sodium        sulfate, filtered and concentrated under reduced pressure to        give quantitatively        2-(5-chloro-2H-benzotriazol-2-yl)-1-methoxyethanol    -   c. To a solution of        2-(5-chloro-2H-benzotriazol-2-yl)-1-methoxyethanol (300 mg) in        THF was added a 2 molar solution of ethyl magnesium bromide        Grignard reagent (1.6 mL) at −78° C. under nitrogen and the        mixture let warm slowly to room temperature. The mixture was        quenched with a saturated solution of ammonium chloride,        followed by magnesium sulfate. The resulted solids were filtered        off and the organic layer concentrated under reduced pressure to        give a residue that was purified by chromatography (SiO₂,        heptane/EA) to afford        1-(5-chloro-2H-benzotriazol-2-yl)butan-2-ol (107 mg). Rf=0.7        (2:1 EA/heptane).    -   d. 1-(5-Chloro-2H-benzotriazol-2-yl)butan-2-ol in DCM was        reacted with Dess-Martin periodinane. After stirring at room        temperature, the mixture was concentrated under reduced pressure        and purified by chromatography (SiO₂, heptane/EA) to afford        1-(5-chloro-2H-benzotriazol-2-yl)butan-2-one.

Example 86N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyanopropyl}-4-trifluoromethylthiobenzamide(compound No 1.048)

Using a procedure similar to that described in Example 1, except using2-amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]butyronitrile describedin Example 85 and 4-trifluoromethylbenzoyl chloride, the title compoundwas isolated as a solid. MS (ES): M/Z [M+H]=454. 1H NMR: (400 MHz,CHLOROFORM-d): 1.29 (t, J=7.4 Hz, 3H), 1.77-1.94 (m, J=14.4, 7.4, 7.4,7.3 Hz, 1H), 2.16-2.36 (m, J=14.4, 7.4, 7.4, 7.3 Hz, 1H), 5.23 (d,J=13.9 Hz, 1H), 5.47 (d, J=13.8 Hz, 1H), 7.21 (s, 1H), 7.39 (dd, J=9.1,1.9 Hz, 1H), 7.73-7.79 (m, 2H), 7.79-7.85 (m, 3H) and 7.87 (dd, J=1.8,0.7 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).

Example 87N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-3-methylbutyl}-4-trifluoromethoxybenzamide(compound No 1.049)

Using a procedure similar to that described in Example 1, except using2-amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]-4-methylpentanenitrile,the title compound was isolated as a solid. MS (ES): M/Z [M+H]=466. 1HNMR: (400 MHz, CHLOROFORM-d): 1.11 (d, J=6.4 Hz, 3H), 1.14 (d, J=6.3 Hz,3H), 1.79-1.90 (m, 1H), 2.05-2.21 (m, 2H), 5.27 (d, J=13.8 Hz, 1H), 5.48(d, J=13.8 Hz, 1H), 7.27 (s, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.39 (dd,J=9.1, 1.7 Hz, 1H), 7.78-7.86 (m, 3H) and 7.87 (d, J=1.8 Hz, 1H). 19FNMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]-4-methylpentanenitrilewas prepared using a procedure similar to that described in Example 1,part b, except starting from1-(5-chloro-2H-benzotriazol-2-yl)-4-methylpentan-2-one.1-(5-Chloro-2H-benzotriazol-2-yl)-4-methylpentan-2-one was preparedusing a procedure similar to that described in Example 85, part a to d,except using isopropyl magnesium bromide Grignard reagent in part c.

Example 88N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-3-methylbutyl}-4-trifluoromethylthiobenzamide(compound No 1.050)

Using a procedure similar to that described in Example 1, except using2-amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]-4-methylpentanenitriledescribed in Example 87 and 4-trifluoromethylbenzoyl chloride, the titlecompound was isolated as a solid. 1H NMR: (400 MHz, CHLOROFORM-d): 1.11(d, J=6.5 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H), 1.78-1.91 (m, 1H), 2.06-2.21(m, 2H), 5.27 (d, J=13.8 Hz, 1H), 5.49 (d, J=13.8 Hz, 1H), 7.16 (s, 1H),7.40 (dd, J=9.1, 1.8 Hz, 1H), 7.75-7.80 (m, 2H), 7.80-7.86 (m, 3H) and7.87 (dd, J=1.8, 0.5 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s,3F).

Compounds of Examples 89 and 90 were Prepared According to the FollowingReaction Scheme

Final ProductV=C—H; W=C—Cl; X=C—H; Y=C—H;Q=P=N;R₃=R₄=H; a=1; R₅=t-butyl; R₆=H;Z=C(O); R₇=p-phenyl-R

Example 89N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-2,2-dimethylpropyl}-4-trifluoromethoxybenzamide(compound No 1.051)

Using a procedure similar to that described in Example 1, except using2-amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]-3,3-dimethylbutyronitrile,the bis-amide derivativeN-{1-[(5-chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-2,2-dimethylpropyl}-4-trifluoromethoxy-N-(4-trifluoromethoxybenzoyl)-benzamidewas isolated instead of the title compound. MS (ES): M/Z [M+H]=654.Subsequent treatment with lithium hydroxide in methanol and purificationby chromatography (SiO₂, heptane/EA) afforded the title compound as asolid. MS (ES): M/Z [M+H]=466. 1H NMR: (400 MHz, CHLOROFORM-d): 0.17 (s,9H), 5.34 (d, J=14.1 Hz, 1H), 5.51 (d, J=14.1 Hz, 1H), 7.02 (s, 1H),7.35 (d, J=8.0 Hz, 2H), 7.38 (dd, J=9.1, 1.9 Hz, 1H), 7.79 (dd, J=9.1,0.6 Hz, 1H), 7.84 (dd, J=1.8, 0.6 Hz, 1H) and 7.89 (d, J=8.8 Hz, 2H).19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]-3,3-dimethylbutyronitrilewas prepared using a procedure similar to that described in Example 1,part a and b, except using 1-chloro-3,3-dimethylbutan-2-one instead ofchloroacetone in part a.

Example 90N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-2,2-dimethylpropyl}-4-trifluoromethylthiobenzamide(compound No 1.052)

Using a procedure similar to that described in Example 1, except using2-amino-2-[(5-chloro-2H-benzotriazol-2-yl)methyl]-3,3-dimethylbutyronitriledescribed in Example 89 and 4-trifluoromethylbenzoyl chloride, thebis-amide derivativeN-{1-[(5-chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-2,2-dimethylpropyl}-4-trifluoromethylthio-N-(4-trifluoromethylthiobenzoyl)-benzamidewas isolated instead of the title compound. MS (ES): M/Z [M+H]=686.Subsequent treatment with lithium hydroxide in methanol and purificationby chromatography (SiO₂, heptane/EA) afforded the title compound as asolid. MS (ES): M/Z [M+H]=482. 1H NMR: (400 MHz, CHLOROFORM-d): 1.17 (s,9H), 5.35 (d, J=14.1 Hz, 1H), 5.51 (d, J=14.1 Hz, 1H), 7.06 (s, 1H),7.38 (dd, J=9.1, 1.9 Hz, 1H), 7.75-7.82 (m, 3H), 7.84 (dd, J=1.8, 0.6Hz, 1H) and 7.85-7.91 (m, 2H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3(s, 3F).

Compounds of Examples 91 and 92 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—H; W=C—Cl; X=C—H; Y=C—H;Q=P=N;R₃=R₄=H; a=1; R₅=CH₂OH, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 91N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(hydroxymethyl)ethyl]-4-trifluoromethoxybenzamide(compound No 1.058)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-(hydroxymethyl)propionitrile,the ester derivative 4-trifluoromethoxybenzoic acid2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-cyanopropyl ester wasisolated instead of the title compound. This ester was reacted with more4-trifluoromethoxybenzoyl chloride, subsequently treated with lithiumhydroxide in methanol and purified by chromatography (SiO₂, heptane/EA)to afford the title compound as a solid. MS (ES): M/Z [M+H]=440. 1H NMR:(400 MHz, CHLOROFORM-d): 3.27 (t, J=7.3 Hz, 1H), 3.94 (dd, J=11.9, 7.3Hz, 1H), 4.30 (dd, J=11.9, 5.9 Hz, 1H), 5.43 (d, J=13.9 Hz, 1H), 5.48 (,J=14.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.43 (dd, J=9.1, 1.9 Hz, 1H),7.45 (s, 1H), 7.82-7.89 (m, 3H) and 7.90 (dd, J=1.8, 0.6 Hz, 1H). 19FNMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-(hydroxymethyl)propionitrilewas prepared using a procedure similar to that described in Example 1,part b, except starting from1-(tert-butyldimethylsilyloxy)-3-(5-chloro-2H-benzotriazol-2-yl)-propan-2-onethat was prepared as follows (the tert-butyldimethylsilyl protectinggroup was removed under the Strecker reaction conditions):

-   -   a. To a solution of 2-allyl-5-chloro-2H-benzotriazole (5.2 g),        described in Example 85 part a, in a 10 to 1 mixture of THF and        water (45 mL), was added a 50% solution of        4-methylmorpholine-N-oxide in water (7 mL) followed by a 4%        solution of osmium tetroxide in water (2 mL). After stirring        overnight at room temperature, the mixture was quenched with a        10% solution of sodium thiosulfate, extracted with ethyl        acetate. The organic layer was dried over magnesium sulfate,        filtered and concentrated under reduced pressure to give        3-(5-chloro-2H-benzotriazol-2-yl)-propane-1,2-diol (4.8 g, 79%)        that was used directly into the next step without further        purification.    -   b. To a solution of        3-(5-chloro-2H-benzotriazol-2-yl)-propane-1,2-diol (1.09 g) in        DCM at 0° C. was added imidazole (0.65 g) and        tert-butyldimethylsilyl chloride (0.8 g). After stirring        overnight at room temperature, the mixture was diluted with DCM,        washed with water, dried over magnesium sulfate, filtered and        concentrated under reduced pressure to give a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        1-(tert-butyldimethylsilyloxy)-3-(5-chloro-2H-benzotriazol-2-yl)-propan-2-ol        (1.5 g, 85%). Rf=0.55 (1:1 EA/heptane).    -   c.        1-(tert-Butyldimethylsilyloxy)-3-(5-chloro-2H-benzotriazol-2-yl)-propan-2-ol        (1.5 g) in DCM (20 mL) was reacted with Dess-Martin periodinane        (2.1 g). After stirring overnight at room temperature, the        mixture was concentrated under reduced pressure and purified by        chromatography (SiO₂, heptane/EA) to afford        1-(tert-butyldimethylsilyloxy)-3-(5-chloro-2H-benzotriazol-2-yl)-propan-2-one        (1.2 g).

Example 92N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(hydroxymethyl)ethyl]-4-trifluoromethylthiobenzamide(compound No 1.059)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-(hydroxymethyl)propionitrile,described in Example 91, and 4-trifluoromethylbenzoyl chloride, theester derivative 4-trifluoromethylbenzoic acid2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-cyanopropyl ester wasisolated instead of the title compound. This ester was reacted with more4-trifluoromethylbenzoyl chloride, subsequently treated with lithiumhydroxide in methanol and purified by chromatography (SiO₂, heptane/EA)to afford the title compound as a solid. MS (ES): M/Z [M+H]=456. 1H NMR:(400 MHz, CHLOROFORM-d): 3.31 (br. s., 1H), 3.94 (d, J=11.8 Hz, 1H),4.31 (d, J=11.7 Hz, 1H), 5.43 (d, J=14.0 Hz, 1H), 5.49 (d, J=13.9 Hz,1H), 7.43 (dd, J=9.1, 1.9 Hz, 1H), 7.51 (s, 1H), 7.78 (d, J=8.3 Hz, 2H),7.84-7.87 (m, 3H) and 7.90 (dd, J=1.8, 0.6 Hz, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −42.2 (s, 3F).

Compounds of Examples 93 to 95 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—H; W=C—Cl; X=C—H; Y=C—H;Q=P=N;R₃=R₄=H; a=1; R₅=CH₂X′Me; R₆=H;Z=C(O); R₇=p-phenyl-R; R=OCF₃ or SCF₃

Example 93N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(methylthiomethyl)ethyl]-4-trifluoromethoxybenzamide(compound No 1.061)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-(methylthiomethyl)propionitrile,the title compound was isolated as a solid. MS (ES): M/Z [M+H]=470. 1HNMR: (400 MHz, CHLOROFORM-d): 2.41 (s, 3H), 3.07 (d, J=14.7 Hz, 1H),3.52 (d, J=14.6 Hz, 1H), 5.47 (dd, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.41(dd, J=9.1, 1.8 Hz, 2H) and 7.79-7.94 (m, 5H). 19F NMR (376 MHz,CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-(methylthiomethyl)propionitrilewas prepared using a procedure similar to that described in Example 1,part b, except starting from1-(5-chloro-2H-benzotriazol-2-yl)-3-(methylthio)propan-2-one that wasprepared as follows:

-   -   a. To a solution of 2-allyl-5-chloro-2H-benzotriazole (5.0 g),        described in Example 85 part a, in DCM (50 mL), was added        meta-chloroperbenzoic acid (8.5 g, 55% pure). After stirring at        room temperature for 24 hours, the mixture was filtered through        a plug of basic alumina. The filtrate was concentrated under        reduced pressure to give a residue that was purified by        chromatography (SiO₂, heptane/EA) to afford        5-chloro-2-oxiranylmethyl-2H-benzotriazole (0.7 g). Rf=0.55 (2:1        EA/heptane).    -   b. To a solution of 5-chloro-2-oxiranylmethyl-2H-benzotriazole        (306 mg) in methanol (5 mL) was added sodium thiomethoxide (307        mg). After stirring overnight at room temperature, the mixture        was extracted with ethyl acetate. The organic layer was washed        with water, dried over magnesium sulfate, filtered and        concentrated under reduced pressure to give        1-(5-chloro-2H-benzotriazol-2-yl)-3-(methylthio)propan-2-ol that        was used directly into the next oxidation step.    -   c. 1-(5-Chloro-2H-benzotriazol-2-yl)-3-(methylthio)propan-2-ol        in DCM (5 mL) was reacted with Dess-Martin periodinane (720 mg).        After stirring overnight at room temperature, the mixture was        concentrated under reduced pressure and purified by        chromatography (SiO₂, heptane/EA) to afford        1-(5-chloro-2H-benzotriazol-2-yl)-3-(methylthio)propan-2-one        (149 mg, 40% in two steps).

Example 94N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(methoxymethyl)ethyl]-4-trifluoromethoxybenzamide(compound No 1.062)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-(methoxymethyl)propionitrile,the title compound was isolated as a solid. MS (ES): M/Z [M+H]=454. 1HNMR: (400 MHz, CHLOROFORM-d): 3.52 (s, 3H), 3.71 (d, J=9.8 Hz, 1H), 4.12(d, J=9.7 Hz, 1H), 5.37-5.47 (m, 2H), 7.33 (d, 2H), 7.40 (dd, J=9.1, 1.9Hz, 1H), 7.48 (s, 1H) and 7.81-7.90 (m, 4H). 19F NMR (376 MHz,CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-(methoxymethyl)propionitrilewas prepared using a procedure similar to that described in Example 1,part b, except starting from1-(5-chloro-2H-benzotriazol-2-yl)-3-methoxypropan-2-one.1-(5-Chloro-2H-benzotriazol-2-yl)-3-methoxypropan-2-one was preparedusing a procedure similar to that described in Example 93, part a to c,except using sodium methoxide in part b.

Example 95N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(methanesulfonylmethyl)ethyl]-4-trifluoromethoxybenzamide(compound No 1.063)

To a solution ofN-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(methylthiomethyl)ethyl]-4-trifluoromethoxybenzamide(36 mg) in a mixture of DCM and TFA was added 3 drops of hydrogenperoxide (30% weight in water). After stirring overnight at roomtemperature, the mixture was concentrated under reduced pressure to givethe title compound as a solid. MS (ES): M/Z [M+H]=502. 1H NMR: (400 MHz,DMSO-d₆): 3.03 (s, 3H), 4.13 (d, J=5.0 Hz, 1H), 4.20 (d, J=5.1 Hz, 1H),5.54 (s, 2H), 7.43 (dd, J=9.1, 1.9 Hz, H), 7.50 (d, J=8.7, 0.8 Hz, 2H),7.68 (s, 1H), 7.81-7.90 (m, 2H), 7.91-8.00 (m, 2H), 8.05 (dd, J=1.9, 0.6Hz, 1H) and 8.29 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

Compounds of Examples 96 to 104 were Prepared According to the FollowingGeneral Reaction Scheme

Final ProductV=C—R₈; W=C—R₉; X=C—R₁₀; Y=C—R₁₁;Q=C—R₂; P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 96N-[1-Cyano-1-methyl-2-(5-nitro-2H-indazol-2-yl)ethyl]-4-trifluoromethoxybenzamide(compound No 2.001)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5-nitro-2H-indazol-2-yl)propionitrile (62 mg), thetitle compound was isolated as a white solid (100 mg, 91%). MS (ES): M/Z[M+H]=434. 1H NMR: (400 MHz, DMSO-d₆): 1.72 (s, 3H), 5.21 (q, J=13.7 Hz,2H), 7.53 (d, J=8.2 Hz, 2H), 7.81 (d, J=9.5 Hz, 1H), 7.97 (d, J=8.8 Hz,2H), 8.01 (dd, J=2.2 Hz, 1H), 8.82 (s, 1H), 8.94 (d, J=2.0 Hz, 1H) and8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-2-methyl-3-(5-nitro-2H-indazol-2-yl)propionitrile (444 mg) wasprepared using a procedure similar to that described in Example 1, parta and b, except starting from commercially available 5-nitro-1H-indazole(7 g), one-half molar equivalent of potassium carbonate (3.1 g), oneequivalent of potassium iodide (9.2 g) and heating the reaction mixtureto reflux in acetone to isolate desired1-(5-nitro-2H-indazol-2-yl)propan-2-one (890 mg, 9.5%) along with1-(5-nitro-1H-indazol-1-yl)propan-2-one in part a.

Example 97N-[1-Cyano-1-methyl-2-(5-nitro-2H-indazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide(compound No 2.002)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5-nitro-2H-indazol-2-yl)propionitrile (62 mg,described in Example 96) and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (96 mg, 84%). MS (ES): M/Z[M+H]=450. 1H NMR: (400 MHz, DMSO-d₆): 1.72 (s, 3H), 5.22 (q, 2H), 7.81(d, J=9.5 Hz, 1H), 7.86-7.90 (m, 2H), 7.92-7.97 (m, 2H), 8.00-8.05 (m,1H), 8.83 (s, 1H), 8.95 (d, J=1.9 Hz, 1H) and 9.07 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −41.9 (s, 3F).

Example 98N-[1-Cyano-2-(5,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.003)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,7-dichloro-2H-indazol-2-yl)-2-methylpropionitrile (60 mg),the title compound was isolated as a white solid (80 mg, 78%). MS (ES):M/Z [M+H]=457. 1H NMR: (400 MHz, DMSO-d₆): 1.70 (s, 3H), 5.11 (d, 1H),5.23 (d, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.89 (d, J=1.6 Hz, 1H), 7.97 (d,J=8.8 Hz, 2H), 8.53 (s, 1H), 8.94 (d, J=2.0 Hz, 1H) and 8.95 (s, 1H).19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(5,7-dichloro-2H-indazol-2-yl)-2-methylpropionitrile wasprepared using a procedure similar to that described in Example 1, parta and b, except starting from 5,7-dichloro-1H-indazole (3 g) and heatingthe reaction mixture to reflux in acetone to isolate desired1-(5,7-dichloro-2H-indazol-2-yl)propan-2-one (1.7 g, 44%) along with1-(5,7-dichloro-1H-indazol-1-yl)propan-2-one (1.2 g, 30%) in part a.

5,7-Dichloro-1H-indazole was prepared as follows by adapting proceduresdescribed in the literature for the preparation of indazoles substitutedon the six-membered ring. See for example, R. A. Bartsch, et al. J.Heterocycl. Chem. 1984, 21, 1063 and P. Schumann et al, Bioorganic &Medicinal Chemistry Letters, 2001, 11, 1153.

-   -   a. To a suspension of 2,4-dichloro-6-methylaniline (5 g) in a        mixture of hydrochloric acid (7.5 mL) and water (7.5 mL), was        slowly added at 0° C. a solution of sodium nitrite (2 g) in a        minimal amount of water. After all solid starting materials        disappeared to yield a yellow mixture; a solution of sodium        tetrafluoroborate (4.4 g) in water (10 mL) was added. After        stirring 45 minutes at 0° C., the solids that formed were        filtered, washed with chilled methanol, washed with diethyl        ether and dried under vacuum to yield        2,4-dichloro-6-methylbenzenediazonium tetrafluoroborate (5.7 g).    -   b. A mixture of 2,4-dichloro-6-methylbenzenediazonium        tetrafluoroborate (5.5 g), 18-crown-6 (271 mg) and potassium        acetate (4 g) were stirred in chloroform (60 mL) for 1.5 hours        at room temperature. The resulting crude mixture was extracted        with ethyl acetate, washed with brine, dried over anhydrous        sodium sulfate, filtered and concentrated under reduced pressure        to give 5,7-dichloro-1H-indazole as a pale brown solid (3 g).

Example 99N-[1-Cyano-2-(5,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.005)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5,7-dichloro-2H-indazol-2-yl)propionitrile (60 mg,described in Example 98) and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (80 mg, 76%). MS (ES): M/Z[M+H]=473. 1H NMR: (400 MHz, DMSO-d₆): 1.70 (s, 3H), 5.11 (d, 1H), 5.25(d, 1H), 7.48 (s, 1H), 7.84-7.91 (m, 3H), 7.95 (d, 2H), 8.54 (s, 1H) and9.03 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.0 (s, 3F).

Example 100N-[1-Cyano-2-(5,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-phenoxybenzamide(compound No 2.004)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5,7-dichloro-2H-indazol-2-yl)propionitrile (60 mg,described in Example 98) and 4-phenoxybenzoyl chloride, the titlecompound was isolated as a white solid (90 mg, 87%). MS (ES): M/Z[M+H]=465. 1H NMR: (400 MHz, DMSO-d₆): 1.71 (s, 3H), 5.12 (d, 1H), 5.21(d, 1H), 7.04-7.13 (m, 4H), 7.23 (t, J=7.4 Hz, 1H), 7.41-7.51 (m, 3H),7.85-7.92 (m, 3H), 8.52 (s, 1H) and 8.80 (s, 1H).

Example 101N-[2-(5-Chloro-7-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.006)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-7-methyl-2H-indazol-2-yl)-2-methylpropionitrile (58mg), the title compound was isolated as a white solid (73 mg, 72%). MS(ES): M/Z [M+H]=437. 1H NMR: (400 MHz, DMSO-d₆): 1.69 (s, 3H), 2.39 (s,3H), 5.05 (d, 1H), 5.19 (d, J=13.7 Hz, 1H), 7.03 (s, 1H), 7.52 (d, J=8.2Hz, 2H), 7.65 (d, J=0.8 Hz, 1H), 7.97 (d, J=8.7 Hz, 2H), 8.36 (s, 1H)and 8.89 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(5-chloro-7-methyl-2H-indazol-2-yl)-2-methylpropionitrile wasprepared using a procedure similar to that described in Example 1, parta and b, except starting from 5-chloro-7-methyl-1H-indazole (6.9 g) andheating the reaction mixture to reflux in acetone for 1.5 days to afford1-(5-chloro-7-methyl-2H-indazol-2-yl)propan-2-one (1.9 g) in part a.

5-Chloro-7-methyl-1H-indazole was prepared using a procedure similar tothat described in Example 98, part a and b, except starting from4-chloro-2,6-dimethylaniline (5 g).

Example 102N-[2-(5-Chloro-7-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.007)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5-chloro-7-methyl-2H-indazol-2-yl)propionitrile (58mg, described in Example 101) and 4-trifluoromethylthiobenzoyl chloride,the title compound was isolated as a white solid (77 mg, 73%). MS (ES):M/Z [M+H]=453. 1H NMR: (400 MHz, DMSO-d₆): 1.69 (s, 3H), 2.38 (s, 3H),5.05 (d, 1H), 5.21 (d, 1H), 7.03 (s, 1H), 7.66 (s, 1H), 7.87 (d, 2H),7.94 (d, 2H), 8.37 (s, 1H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−42.0 (s, 3F).

Example 103N-[1-Cyano-2-(5,7-dichloro-3-methyl-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.010)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,7-dichloro-3-methyl-2H-indazol-2-yl)-2-methylpropionitrile(40 mg), the title compound was isolated as a white solid (60 mg, 90%).MS (ES): M/Z [M+H]=471. 1H NMR: (400 MHz, DMSO-d₆): 1.82 (s, 3H), 2.73(s, 3H), 4.98 (d, 1H), 5.08 (d, J=13.7 Hz, 1H), 7.45 (dd, 1H), 7.52 (d,2H), 7.91 (d, 1H), 8.00-8.04 (m, 2H) and 9.09 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(5,7-dichloro-3-methyl-2H-indazol-2-yl)-2-methylpropionitrilewas prepared using a procedure similar to that described in Example 1,part a and b, except starting from 5,7-dichloro-3-methyl-1H-indazole(400 mg) and heating the reaction mixture to reflux in acetone to afford1-(5,7-dichloro-3-methyl-2H-indazol-2-yl)propan-2-one (140 mg) in parta.

5,7-Dichloro-3-methyl-1H-indazole was prepared using a procedure similarto that described in Example 98, part a and b, except starting from2,4-dichloro-6-ethylaniline (2.9 g) that was prepared by chlorination of6-ethylaniline (10 g) with N-chlorosuccinimide (22 g) in acetonitrile(80 mL).

Example 104N-[2-(5,7-Dichloro-3-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.011)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(5,7-dichloro-3-methyl-2H-indazol-2-yl)propionitrile(40 mg, described in Example 103) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (64 mg, 92%).MS (ES): M/Z [M+H]=487. 1H NMR: (400 MHz, DMSO-d₆): 1.83 (s, 3H), 2.73(s, 3H), 5.00 (d, 1H), 5.06 (d, 1H), 7.45 (dd, J=1.6 Hz, 1H), 7.87 (d,J=8.2 Hz, 2H), 7.91 (dd, J=1.6 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H) and 9.16(s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.0 (s, 3F).

Compounds of Examples 105 to 131 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=C—R₈; W=C—R₉; X=C—R₁₀; Y=C—R₁₁;Q=C—R₂; P=N;R₂=O—C₁-C₄-alkyl, O—C₁-C₄-alkyl-O—C₁-C₄-alkyl, O—C₁-C₄—NH—C₁-C₄-alkyl,O—C₁-C₄—N(C₁-C₄-alkyl)₂;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 105N-[2-(6-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.008)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (40mg), the title compound was isolated as a white solid (60 mg, 88%). MS(ES): M/Z [M+H]=453. 1H NMR: (400 MHz, DMSO-d₆): 1.71 (s, 3H), 4.19 (s,3H), 4.76 (d, 1H), 4.88 (d, 1H), 6.87 (dd, J=9.0, 1.7 Hz, 1H), 7.50-7.55(m, 3H), 7.89 (d, J=9.1 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H) and 8.92 (s,1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(6-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile(475 mg, 93%) was prepared using a procedure similar to that describedin Example 1, part b, except starting from1-(6-chloro-3-methoxy-2H-indazol-2-yl)propan-2-one (462 mg) that wasprepared as follows:

-   -   a. To a solution of 4-chloro-2-nitrobenzaldehyde (4 g) in        dioxane (35 mL), was added        2-(tert-butyldimethylsilanyloxy)propylamine (6.1 g, 1.5        equivalent) in methanol (15 mL) followed by acid acetic (1.9 mL)        in methanol (15 mL). After overnight stirring at room        temperature, a molar solution of sodium cyanoborohydride in THF        (22 mL) was added. After 30 minutes, the reaction mixture was        quenched with water and extracted with ethyl acetate. The        organic phase was dried over anhydrous magnesium sulfate,        filtered and concentrated under reduced pressure to yield a        residue that was purified by chromatography (SiO₂, heptane/EA)        to afford        [2-(tert-butyldimethylsilanyloxy)propyl]-(4-chloro-2-nitrobenzyl)amine        (5.9 g, 77%). 2-(tert-Butyldimethylsilanyloxy)propylamine was        obtained by reacting 1-aminopropan-2-ol with        2-tert-butyldimethylsilyl chloride and imidazole in DCM for two        hours at room temperature followed by an aqueous work-up.    -   b. Potassium hydroxide (0.72 g) was added to a stirred solution        of        [2-(tert-butyldimethylsilanyloxy)propyl]-(4-chloro-2-nitrobenzyl)amine        (3 g) in methanol (30 mL). After overnight stirring at 60° C.,        the reaction mixture was quenched with water and extracted with        ethyl acetate. The organic phase was dried over anhydrous        magnesium sulfate, filtered and concentrated under reduced        pressure to yield a residue that was purified by chromatography        (SiO₂, heptane/EA) to afford        2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-3-methoxy-2H-indazole        (2.2 g, 87%).    -   c. To a solution of        2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-3-methoxy-2H-indazole        (1 g) in THF (35 mL), was added a solution of tert-butylammonium        fluoride (1M in THF, 3 mL). After stirring at room temperature        for 1.5 hours, the reaction mixture was quenched with water and        extracted with ethyl acetate. The organic phase was dried over        anhydrous magnesium sulfate, filtered and concentrated under        reduced pressure to afford quantitatively        1-(6-chloro-3-methoxy-2H-indazol-2-yl)-propan-2-ol as a solid        (0.85 g).    -   d. A solution of dimethyl sulfoxide (1 mL) in DCM was added at        −78° C. to a solution of oxalyl chloride (0.6 mL) in DCM. After        stirring for 30 minutes at −78° C., a solution of        1-(6-chloro-3-methoxy-2H-indazol-2-yl)-propan-2-ol (0.85 g) in        DCM was added. After stirring for 30 minutes at −78° C.,        diisopropylethylamine (3.4 mL) was added and after 30 additional        minutes, the reaction mixture was allowed to warm to room        temperature over 1.5 hours before being concentrated down under        reduced pressure. The reaction mixture residue was taken into a        mixture of ethyl acetate and brine. The organic phase was dried        over anhydrous magnesium sulfate, filtered and concentrated        under reduced pressure to yield a residue that was purified by        chromatography (SiO₂, heptane/EA) to afford        1-(6-chloro-3-methoxy-2H-indazol-2-yl)-propan-2-one as a solid        (0.46 g, 55%).

Alternatively,[2-(tert-butyldimethylsilanyloxy)propyl]-(4-chloro-2-nitrobenzyl)aminedescribed in part a, was prepared as follows:

-   -   e. To a suspension of        2-(tert-butyldimethylsilanyloxy)propylamine (9 equivalents) in        THF was slowly added 4-chloro-2-nitrobenzyl chloride in THF        under vigorous stirring. After overnight stirring at room        temperature, the mixture was concentrated under reduced pressure        to give a residue that was triturated in diethyl ether and        filtered. The ether fractions were collected and concentrated        under reduced pressure to yield a residue that was purified by        chromatography (SiO₂, heptane/EA) to afford        [2-(tert-butyldimethylsilanyloxy)propyl]-(4-chloro-2-nitrobenzyl)amine.

Example 106N-[2-(6-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.009)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (40mg, described in Example 105) and 4-trifluoromethylthiobenzoyl chloride,the title compound was isolated as a white solid (65 mg, 91%). MS (ES):M/Z [M+H]=469. 1H NMR: (400 MHz, DMSO-d₆): 1.71 (s, 3H), 4.20 (s, 3H),4.76 (d, 1H), 4.89 (d, 1H), 6.87 (dd, J=9.0, 1.7 Hz, 1H), 7.51 (s, 1H),7.86-7.91 (m, 3H), 7.97 (d, 2H) and 9.01 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −41.9 (s, 3F).

Example 107N-[2-(5-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.012)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (57mg), the title compound was isolated as a white solid (84 mg, 86%). MS(ES): M/Z [M+H]=453. 1H NMR: (400 MHz, DMSO-d₆): 1.70 (s, 3H), 4.18 (s,3H), 4.77 (d, 1H), 4.90 (d, 1H), 7.16 (dd, J=9.3, 1.6 Hz, 1H), 7.46 (d,J=9.2 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.94 (d, J=0.9 Hz, 1H), 7.98 (d,J=8.7 Hz, 2H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s,3F).

2-Amino-3-(5-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile(114 mg, 73%) was prepared using a procedure similar to that describedin Example 1, part b, except starting from1-(5-chloro-3-methoxy-2H-indazol-2-yl)propan-2-one (140 mg).1-(5-chloro-3-methoxy-2H-indazol-2-yl)propan-2-one was prepared using aprocedure similar to that described in Example 105 part a to d exceptusing 5-chloro-2-nitrobenzaldehyde (2 g) and sodiumtriacetoxyborohydride (3.4 g) in part a to yield[2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-2-nitrobenzyl)amine(2.2 g, 56%).

Example 108N-[2-(5-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.013)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (57mg, described in Example 107) and 4-trifluoromethylthiobenzoyl chloride,the title compound was isolated as a white solid (96 mg, 95%). MS (ES):M/Z [M+H]=469. 1H NMR: (400 MHz, DMSO-d₆): 1.70 (s, 3H), 4.19 (s, 3H),4.77 (d, 1H), 4.90 (d, 1H), 7.16 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.4 Hz,1H), 7.87 (d, J=8.0 Hz, 2H), 7.92-8.01 (m, 3H) and 9.00 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −41.9 (s, 3F).

Example 109N-[2-(5-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.014)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (52mg), the title compound was isolated as a white solid (85 mg, 97%). MS(ES): M/Z [M+H]=467. 1H NMR: (400 MHz, DMSO-d₆): 1.27 (t, J=7.0 Hz, 3H),1.71 (s, 3H), 4.52 (q, J=6.9 Hz, 2H), 4.78 (d, 1H), 4.92 (d, 1H), 7.16(dd, J=9.3, 2.0 Hz, 1H), 7.47 (d, J=9.3 Hz, 1H), 7.52 (d, J=8.2 Hz, 2H),7.87 (d, J=1.5 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H) and 8.91 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(5-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (104mg, 72%) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(5-chloro-3-ethoxy-2H-indazol-2-yl)propan-2-one (131 mg).1-(5-chloro-3-ethoxy-2H-indazol-2-yl)propan-2-one was prepared using aprocedure similar to that described in Example 105 part a to d exceptusing 5-chloro-2-nitrobenzaldehyde (2 g) and sodiumtriacetoxyborohydride (3.4 g) in part a and using ethanol instead ofmethanol in part b.

Example 110N-[2-(5-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.015)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (52mg, described in Example 109) and 4-trifluoromethylthiobenzoyl chloride,the title compound was isolated as a white solid (83 mg, 93%). MS (ES):M/Z [M+H]=483. 1H NMR: (400 MHz, DMSO-d₆): 1.26 (t, J=7.0 Hz, 3H), 1.71(s, 3H), 4.52 (q, J=7.0 Hz, 2H), 4.78 (d, 1H), 4.93 (d, 1H), 7.16 (dd,J=9.3, 1.9 Hz, 1H), 7.47 (d, J=9.3 Hz, 1H), 7.85-7.89 (m, 3H), 7.96 (d,J=8.8 Hz, 2H) and 8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.0 (s,3F).

Example 111N-[1-Cyano-2-(3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.016)

Using a procedure similar to that described in Example 1, except using2-amino-3-(3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (52 mg), thetitle compound was isolated as a white solid (140 mg, 77%). MS (ES): M/Z[M+H]=419. 1H NMR: (400 MHz, DMSO-d₆): 1.72 (s, 3H), 4.19 (s, 3H), 4.77(d, 1H), 4.90 (d, 1H), 6.88 (d, J=1.2 Hz, 1H), 7.19 (d, J=6.7 Hz, 1H),7.41 (d, J=8.9 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H),8.00 (d, J=8.7 Hz, 2H) and 8.95 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−57.1 (s, 3F).

2-Amino-3-(3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (130 mg,83%) was prepared using a procedure similar to that described in Example1, part b, except starting from1-(3-methoxy-2H-indazol-2-yl)propan-2-one (138 mg).1-(3-methoxy-2H-indazol-2-yl)propan-2-one was prepared using a proceduresimilar to that described in Example 105 part a to d except startingfrom 2-nitrobenzaldehyde (2.5 g) in part a.

Example 112N-{2-[6-Chloro-3-(2-methoxyethoxy)-2H-indazol-2-yl]-1-cyano-1-methylethyl}-4-trifluoromethoxybenzamide(compound No 2.017)

Using a procedure similar to that described in Example 1, except using2-amino-3-[6-chloro-3-(2-methoxyethoxy)-2H-indazol-2-yl]-2-methylpropionitrile(60 mg), the title compound was isolated as a white solid (41 mg, 43%).MS (ES): M/Z [M+H]=497. 1H NMR: (400 MHz, DMSO-d₆): 1.70 (s, 3H), 3.27(s, 3H), 3.61 (dd, J=5.2, 3.7 Hz, 2H), 4.58 (dd, J=4.9, 3.9 Hz, 2H),4.79 (d, 1H), 4.92 (d, 1H), 6.90 (dd, J=9.0, 1.8 Hz, 1H), 7.53-7.55 (m,3H), 7.82 (d, J=9.1 Hz, 1H), 7.98 (d, 2H) and 8.93 (s, 1H). 19F NMR (376MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-[6-chloro-3-(2-methoxyethoxy)-2H-indazol-2-yl]-2-methylpropionitrile(60 mg, 61%) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-[6-chloro-3-(2-methoxyethoxy)-2H-indazol-2-yl]propan-2-one (90 mg).1-[6-Chloro-3-(2-methoxyethoxy)-2H-indazol-2-yl]propan-2-one wasprepared using a procedure similar to that described in Example 105 parta to d except using 2-methoxyethanol instead of methanol in part b.

Example 113N-{2-[6-Chloro-3-(2-dimethylaminoethoxy)-2H-indazol-2-yl]-1-cyano-1-methylethyl}-4-trifluoromethoxybenzamide(compound No 2.018)

Using a procedure similar to that described in Example 1, except using2-amino-3-[6-chloro-3-(2-dimethylaminoethoxy)-2H-indazol-2-yl]-2-methylpropionitrile(60 mg), the title compound was isolated as a white solid (44 mg, 46%).MS (ES): M/Z [M+H]=510. 1H NMR: (400 MHz, CHLOROFORM-d): 1.90 (s, 3H),2.43 (s, 6H), 2.85 (dd, J=5.8, 4.8 Hz, 1H), 2.95 (dd, J=6.9, 4.8 Hz,1H), 4.52 (d, J=14.2 Hz, 1H), 4.69 (ddd, J=10.3, 5.7, 4.9 Hz, 1H), 4.80(ddd, J=10.2, 6.9, 4.7 Hz, 1H), 4.90 (d, J=14.2 Hz, 1H), 6.92 (dd,J=9.1, 1.7 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.47 (dd, J=1.6, 0.6 Hz,1H), 7.64 (dd, J=9.0, 0.6 Hz, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-[6-chloro-3-(2-dimethylaminoethoxy)-2H-indazol-2-yl]-2-methylpropionitrile(127 mg, 78%) was prepared using a procedure similar to that describedin Example 1, part b, except starting from1-[6-chloro-3-(2-dimethylaminoethoxy)-2H-indazol-2-yl]propan-2-one (150mg). 1-[6-Chloro-3-(2-dimethylaminoethoxy)-2H-indazol-2-yl]propan-2-onewas prepared using a procedure similar to that described in Example 105part a to d except using 2-dimethylaminoethanol instead of methanol inpart b.

Example 114N-[1-Cyano-2-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.020)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile(196 mg), the title compound was isolated as a white solid (147 mg,46%). MS (ES): M/Z [M+H]=487. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s,3H), 4.42 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H),7.31 (d, 2H), 7.35 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 8.01-8.10(m, 2H) and 9.13 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s,3F).

2-Amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrilewas prepared using a procedure similar to that described in Example 1,part b, except starting from1-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one.1-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one was preparedusing a procedure similar to that described in Example 105 part a to dexcept using 3,5-dichloro-2-nitrobenzaldehyde (2.1 g) and decaborane(0.41 g) in part a to yield[2-(tert-butyldimethylsilanyloxy)propyl]-(3,5-dichloro-2-nitrobenzyl)amine(1.2 g, 32%). 3,5-Dichloro-2-nitrobenzaldehyde (2.2 g, 79%) was preparedby nitration of 3,5-dichlorobenzaldehyde (2.2 g) in a mixture of nitricacid (1.5 mL) and sulfuric acid (8 mL) at 0° C. for 30 minutes.

Example 115N-[1-Cyano-2-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.019)

Using a procedure similar to that described in Example 1, except using2-amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile(181 mg, described in Example 114) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (161 mg,51%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s,3H), 4.42 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.88 (d, J=14.2 Hz, 1H),7.35 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H),8.02-8.09 (m, 2H) and 9.21 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d):−42.4 (s, 3F).

Example 116N-[1-Cyano-2-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.021)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile(30 mg), the title compound was isolated as a white solid (45 mg, 92%).MS (ES): M/Z [M+H]=487. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 4.12(s, 3H), 4.94 (s, 2H), 7.17 (d, J=1.3 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H),7.63 (d, J=1.2 Hz, 1H), 7.98 (d, J=8.7 Hz, 2H) and 8.95 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile(60 mg, 32%) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one (170 mg).1-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one was preparedusing a procedure similar to that described in Example 105 part a to dexcept using 2,4-dichloro-6-nitrobenzaldehyde (1 g) in part a to yield[2-(tert-butyldimethylsilanyloxy)propyl]-(2,4-dichloro-6-nitrobenzyl)amine(0.6 g, 37%). 2,4-Dichloro-6-nitrobenzaldehyde was prepared as follows:

-   -   a. To a solution of 1,3-dichloro-5-nitrobenzene (7.7 g) and        chloroform (4 mL) in a mixture of THF and DMF (1:1.5, 100 mL),        was slowly added at −78° C. a one molar solution of sodium        hexamethyldisilazane (NaHMDS) in THF (7.7 mL). After stirring        for 30 minutes, the reaction was quenched at −78° C. with a        methanolic solution of hydrochloric acid and let warm to room        temperature. The reaction mixture was extracted with ethyl        acetate. The organic phase was dried over anhydrous magnesium        sulfate, filtered and concentrated under reduced pressure to        yield a residue that contained 70% of        1,5-dichloro-2-dichloromethyl-3-nitrobenzene.    -   b. A mixture of 1,5-dichloro-2-dichloromethyl-3-nitrobenzene        (5.8 g, 70% pure) and zinc dichloride in formic acid (85%) was        heated under reflux for 14 hours. The reaction mixture was        concentrated under reduced pressure to yield a residue that was        poured into water and extracted with ethyl acetate. The organic        phase was dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to yield a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        2,4-dichloro-6-nitrobenzaldehyde as a solid (2.9 g, 87% pure).        1H NMR: (400 MHz, CHLOROFORM-d): 7.76 (d, J=1.9 Hz, 1H), 7.93        (d, J=1.9 Hz, 1H) and 10.32 (s, 1H).

Example 117N-[1-Cyano-2-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.022)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile(30 mg, described in Example 116) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (42 mg, 83%).MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, DMSO-d₆): 1.75 (s, 3H), 4.12(s, 3H), 4.94 (d, J=6.5 Hz, 2H), 7.17 (d, J=1.2 Hz, 1H), 7.62 (d, J=1.1Hz, 1H), 7.86-7.91 (m, 2H), 7.93-7.99 (m, 2H) and 9.03 (s, 1H). 19F NMR(376 MHz, DMSO-d₆): −41.9 (s, 3F).

Example 118N-[2-(6-Bromo-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.023)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-bromo-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (50mg), the title compound was isolated as a white solid (73 mg, 90%). MS(ES): M/Z [M+H]=497. 1H NMR: (400 MHz, DMSO-d₆): 1.71 (s, 3H), 4.19 (s,3H), 4.76 (d, 1H), 4.88 (d, 1H), 6.97 (dd, J=9.0, 1.4 Hz, 1H), 7.53 (d,J=8.3 Hz, 2H), 7.68 (d, J=0.8 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.98 (d,J=8.7 Hz, 2H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s,3F).

2-Amino-3-(6-bromo-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile wasprepared using a procedure similar to that described in Example 1, partb, except starting from1-(6-bromo-3-methoxy-2H-indazol-2-yl)propan-2-one.1-(6-bromo-3-methoxy-2H-indazol-2-yl)propan-2-one was prepared using aprocedure similar to that described in Example 105 part a to d exceptusing 4-bromo-2-nitrobenzaldehyde (5.1 g) and decaborane (0.81 g) inpart a to yield[2-(tert-butyldimethylsilanyloxy)propyl]-(4-bromo-2-nitrobenzyl)amine(3.4 g).

Example 119N-[2-(6-Bromo-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.024)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-bromo-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (50mg, described in Example 118) and 4-trifluoromethylthiobenzoyl chloride,the title compound was isolated as a white solid (80 mg, 96%). MS (ES):M/Z [M+H]=513. 1H NMR: (400 MHz, DMSO-d₆): 1.71 (s, 3H), 4.19 (s, 3H),4.77 (d, 1H), 4.89 (d, 1H), 6.97 (dd, J=9.1, 1.5 Hz, 1H), 7.68 (d, J=0.9Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.86-7.91 (m, 2H), 7.94-7.99 (m, 2H)and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −41.9 (s, 3F).

Example 120N-[1-Cyano-2-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.025)

Using a procedure similar to that described in Example 1, except using2-amino-3-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-2-methylpropionitrile(50 mg), the title compound was isolated as a white solid (62 mg, 77%).MS (ES): M/Z [M+H]=487. 1H NMR: (400 MHz, DMSO-d₆): 1.72 (s, 3H), 4.23(s, 3H), 4.85 (d, 1H), 4.97 (d, 1H), 7.08 (dd, J=9.0, 1.1 Hz, 1H), 7.53(d, J=8.2 Hz, 2H), 7.86 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.09 (d, J=9.0Hz, 1H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −61.8 (s, 3F) and−57.1 (s, 3F).

2-Amino-3-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-2-methylpropionitrilewas prepared using a procedure similar to that described in Example 1,part b, except starting from1-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)propan-2-one.1-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)propan-2-one was preparedusing a procedure similar to that described in Example 105 part a to dexcept using 2-nitro-4-(trifluoromethyl)benzaldehyde (1 g) in part a toyield[2-(tert-butyldimethylsilanyloxy)propyl]-[2-nitro-4-(trifluoromethyl)benzyl]amine(0.6 g, 33%).

Example 121 NN-[1-Cyano-2-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.026)

Using a procedure similar to that described in Example 1, except using2-amino-3-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-2-methylpropionitrile(50 mg, described in Example 120) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (66 mg, 78%).MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, DMSO-d₆): 1.72 (s, 3H), 4.24(s, 3H), 4.84 (d, J=13.8 Hz, 1H), 4.96 (d, J=13.9 Hz, 1H), 7.08 (dd,J=9.0, 1.4 Hz, 1H), 7.85 (s, 1H), 7.88 (d, J=8.2 Hz, 2H), 7.94-7.99 (m,2H), 8.09 (d, J=9.0 Hz, 1H) and 8.99 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −42.0 (s, 3F) and −61.8 (s, 3F).

Example 122N-[2-(6-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.027)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (113mg), the title compound was isolated as a white solid (95 mg, 50%). MS(ES): M/Z [M+H]=467. 1H NMR: (400 MHz, CHLOROFORM-d): 1.58 (t, J=7.1 Hz,3H), 1.91 (s, 3H), 4.50 (d, J=14.2 Hz, 1H), 4.63-4.81 (m, 2H), 4.83 (d,J=14.1 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H),7.46 (d, J=1.1 Hz, 1H), 7.62 (d, J=9.1 Hz, 1H), 7.89-8.02 (m, 2H) and9.07 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (221mg, 95%) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(6-chloro-3-ethoxy-2H-indazol-2-yl)propan-2-one (210 mg).1-(6-chloro-3-ethoxy-2H-indazol-2-yl)propan-2-one was prepared using aprocedure similar to that described in Example 105 part a to d exceptusing 4-chloro-2-nitrobenzaldehyde (21.7 g) and decaborane (4.2 g) inpart a and using ethanol instead of methanol in part b.

Example 123N-[2-(6-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.028)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (108mg, described in Example 122) and 4-trifluoromethylthiobenzoyl chloride,the title compound was isolated as a white solid (96 mg, 51%). MS (ES):M/Z [M+H]=483. 1H NMR: (400 MHz, CHLOROFORM-d): 1.59 (t, J=7.0 Hz, 3H),1.91 (s, 3H), 4.50 (d, J=14.2 Hz, 1H), 4.63-4.81 (m, 2H), 4.83 (d,J=14.2 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H),7.62 (d, J=9.0 Hz, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.90-7.99 (m, 2H) and9.15 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).

Example 124N-[2-(6-Chloro-3-propoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.029)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-propoxy-2H-indazol-2-yl)-2-methylpropionitrile(103 mg), the title compound was isolated as a white solid (104 mg,54%). MS (ES): M/Z [M+H]=481. 1H NMR: (400 MHz, CHLOROFORM-d): 1.14 (t,J=7.4 Hz, 3H), 1.90 (s, 3H), 1.92-2.03 (m, 2H), 4.51 (d, J=14.1 Hz, 1H),4.55-4.69 (m, 2H), 4.81 (d, J=14.1 Hz, 1H), 6.91 (dd, J=9.1, 1.7 Hz,1H), 7.34 (dd, J=8.8, 0.8 Hz, 2H), 7.46 (dd, J=1.7, 0.6 Hz, 1H), 7.62(dd, J=9.1, 0.6 Hz, 1H), 7.90-8.01 (m, 2H) and 9.10 (s, 1H). 19F NMR(376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-chloro-3-propoxy-2H-indazol-2-yl)-2-methylpropionitrile(207 mg, 92%) was prepared using a procedure similar to that describedin Example 1, part b, except starting from1-(6-chloro-3-propoxy-2H-indazol-2-yl)propan-2-one (205 mg).1-(6-chloro-3-propoxy-2H-indazol-2-yl)propan-2-one was prepared using aprocedure similar to that described in Example 105 part a to d exceptusing 4-chloro-2-nitrobenzaldehyde (21.7 g) and decaborane (4.2 g) inpart a and using n-propanol instead of methanol in part b.

Example 125N-[2-(6-Chloro-3-propoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.030)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-propoxy-2H-indazol-2-yl)-2-methylpropionitrile(104 mg, described in Example 124) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (88 mg, 46%).MS (ES): M/Z [M+H]=497. 1H NMR: (400 MHz, CHLOROFORM-d): 1.14 (t, J=7.4Hz, 3H), 1.90 (s, 3H), 1.92-2.04 (m, 2H), 4.51 (d, J=14.2 Hz, 1H),4.56-4.70 (m, 2H), 4.82 (d, J=14.2 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz,1H), 7.47 (d, J=1.7 Hz, 1H), 7.62 (dd, J=9.1, 0.5 Hz, 1H), 7.79 (dd,J=8.3 Hz, 2H), 7.91-7.99 (m, 2H) and 9.17 (s, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −42.3 (s, 3F).

Example 126N-[2-(6-Chloro-3-butoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.031)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-butoxy-2H-indazol-2-yl)-2-methylpropionitrile (88mg), the title compound was isolated as a white solid (60 mg, 43%). MS(ES): M/Z [M+H]=495. 1H NMR: (400 MHz, CHLOROFORM-d): 1.04 (t, J=7.4 Hz,3H), 1.51-1.65 (m, 2H), 1.89 (s, 3H), 1.89-1.98 (m, 2H), 4.51 (d, J=14.2Hz, 1H), 4.57-4.73 (m, 2H), 4.81 (d, J=14.2 Hz, 1H), 6.91 (dd, J=9.1,1.7 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.46 (d, J=1.1 Hz, 1H), 7.62 (dd,J=9.1, 0.5 Hz, 1H), 7.91-8.00 (m, 2H) and 9.09 (s, 1H). 19F NMR (376MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-chloro-3-butoxy-2H-indazol-2-yl)-2-methylpropionitrile (88mg) was prepared using a procedure similar to that described in Example1, part b, except starting from1-(6-chloro-3-butoxy-2H-indazol-2-yl)propan-2-one (79 mg).1-(6-chloro-3-butoxy-2H-indazol-2-yl) propan-2-one was prepared using aprocedure similar to that described in Example 105 part a to d exceptusing 4-chloro-2-nitrobenzaldehyde (21.7 g) and decaborane (4.2 g) inpart a and using n-butanol instead of methanol in part b.

Example 127 Methyl2-[2-cyano-2-methyl-2-(4-trifluoromethoxybenzoylamino)ethyl]-3-methoxy-2H-indazole-6-carboxylate(compound No 2.032)

Using a procedure similar to that described in Example 1, except usingmethyl2-(2-amino-2-cyano-2-methylethyl)-3-methoxy-2H-indazole-6-carboxylate(88 mg), the title compound was isolated as a white solid (126 mg, 86%).MS (ES): M/Z [M+H]=477. 1H NMR: (400 MHz, DMSO-d₆): 1.72 (s, 3H), 3.87(s, 3H), 4.21 (s, 3H), 4.83 (d, 1H), 4.97 (d, 1H), 7.37 (d, J=8.9 Hz,1H), 7.53 (d, J=8.3 Hz, 2H), 7.93-8.03 (m, 3H), 8.07 (s, 1H) and 8.92(s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

Methyl2-(2-amino-2-cyano-2-methylethyl)-3-methoxy-2H-indazole-6-carboxylatewas prepared using a procedure similar to that described in Example 1,part b, except starting from methyl3-methoxy-2-(2-oxo-propyl)-2H-indazole-6-carboxylate. 1 Methyl3-methoxy-2-(2-oxo-propyl)-2H-indazole-6-carboxylate was prepared usinga procedure similar to that described in Example 105 part a to d exceptusing methyl 4-formyl-3-nitrobenzoate (2 g) in part a to yield methyl4-{[2-(tert-butyldimethylsilanyloxy)propylamino]-methyl}-3-nitrobenzoate(2.83 g, 77%). In the basic cyclisation step in part b, desired methyl2-[2-(tert-butyldimethylsilanyloxy)-propyl]-3-methoxy-2H-indazole-6-carboxylate(230 mg) was isolated along with2-[2-(tert-butyldimethylsilanyloxy)propyl]-3-hydroxy-2H-indazole-6-carboxylicacid (781 mg).

Example 128N-[1-Cyano-2-(3-methoxy-6-nitro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.033)

Using a procedure similar to that described in Example 1, except using2-amino-3-(3-methoxy-6-nitro-2H-indazol-2-yl)-2-methylpropionitrile (63mg), the title compound was isolated as a white solid (84 mg, 79%). MS(ES): M/Z [M+H]=464. 1H NMR: (400 MHz, DMSO-d₆): 1.73 (s, 3H), 4.25 (s,3H), 4.88 (d, 1H), 5.00 (d, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.61 (dd,J=9.3, 1.9 Hz, 1H), 7.99 (d, J=8.7 Hz, 2H), 8.12 (d, J=9.3 Hz, 1H), 8.42(d, J=1.6 Hz, 1H) and 8.93 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1(s, 3F).

2-Amino-3-(3-methoxy-6-nitro-2H-indazol-2-yl)-2-methylpropionitrile wasprepared using a procedure similar to that described in Example 1, partb, except starting from1-(3-methoxy-6-nitro-2H-indazol-2-yl)propan-2-one.1-(3-Methoxy-6-nitro-2H-indazol-2-yl)propan-2-one was prepared using aprocedure similar to that described in Example 105 part a to d exceptusing 2,4-dinitrobenzaldehyde (2 g) in part a to yield[2-(tert-butyldimethylsilanyloxy)propyl]-(2,4-dinitrobenzyl)amine (2.6g, 64%).

Example 129N-[2-(6-Amino-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.034)

A mixture ofN-[1-cyano-2-(3-methoxy-6-nitro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(30 mg) described in Example 128 and palladium on charcoal in methanol(2 mL) were stirred at room temperature under hydrogen for 2.5 hours.The reaction mixture was filtered through a plug of Celite® andconcentrated under reduced pressure to yield a residue that was purifiedby chromatography (SiO₂, heptane/EA) to afford the title compound as awhite solid (18 mg, 64%). MS (ES): M/Z [M+H]=434. 1H NMR: (400 MHz,CHLOROFORM-d): 1.88 (s, 3H), 4.38 (s, 3H), 4.41 (d, 1H), 4.72 (d, J=14.2Hz, 1H), 6.48 (dd, J=9.0, 1.8 Hz, 1H), 6.53 (d, J=1.2 Hz, 1H), 7.31 (d,J=8.3 Hz, 2H), 7.55 (d, J=9.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 2H) and 9.43(s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.0 (s, 3F).

Example 130N-[2-(6-Acetylamino-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.035)

Using a procedure similar to that described in Example 1, except usingN-[2-(6-amino-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(23 mg, described in Example 129) and acetyl chloride, the titlecompound was isolated as a white solid (8 mg, 32%). MS (ES): M/Z[M+H]=476. 1H NMR: (400 MHz, DMSO-d₆): 1.71 (s, 3H), 2.05 (s, 3H), 4.16(s, 3H), 4.71 (d, 1H), 4.82 (d, 1H), 6.88 (dd, J=9.2, 1.6 Hz, 1H), 7.52(d, J=8.0 Hz, 2H), 7.74 (d, J=9.1 Hz, 1H), 7.86 (s, 1H), 7.99 (d, J=8.8Hz, 2H), 8.95 (s, 1H) and 9.89 (s, 1H). 19F NMR (376 MHz, DMSO-d₆):−57.1 (s, 3F).

Example 131 Methyl2-[2-cyano-2-methyl-2-(4-trifluoromethoxybenzoylamino)ethyl]-3-methoxy-2H-indazole-6-carboxamide(compound No 2.036)

A solution of methyl2-[2-cyano-2-methyl-2-(4-trifluoromethoxybenzoylamino)ethyl]-3-methoxy-2H-indazole-6-carboxylate(50 mg, described in Example 127) in methanol (3 mL) was stirred withammonium hydroxide (1.5 mL) at room temperature for 8 days. The reactionmixture was concentrated under reduced pressure to yield a residue thatwas purified by chromatography (SiO₂, heptane/EA) to afford the titlecompound as a white solid (3 mg). MS (ES): M/Z [M+H]=462. 1H NMR: (400MHz, METHANOL-d₄): 1.81 (s, 3H), 4.32 (s, 3H), 4.82 (d, 1H), 5.08 (d,J=14.0 Hz, 1H), 7.38 (dd, J=9.0, 1.4 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H),7.90 (d, J=9.0 Hz, 1H), 7.97 (d, J=8.9 Hz, 2H) and 7.99 (s, 1H). 19F NMR(376 MHz, METHANOL-d₄): −59.8 (s, 3F).

Compounds of Examples 132 to 137 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=C—R₈; W=C—H; X=C—R₁₀; Y=C—R₁₁;Q=C—H; P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 132N-[2-(6-Chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.037)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg), thetitle compound was isolated as a white solid (34 mg, 93%). MS (ES): M/Z[M+H]=423. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s, 3H), 4.81 (d, 1H),4.89 (d, 1H), 7.11 (dd, J=8.9, 1.7 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.65(d, J=8.9 Hz, 1H), 7.69 (s, 1H), 7.90 (d, J=8.7 Hz, 2H), 8.17 (s, 1H)and 8.49 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-chloro-2H-indazol-2-yl)-2-methylpropionitrile (54 mg, 79%)was prepared using a procedure similar to that described in Example 1,part b, except starting from 1-(6-chloro-2H-indazol-2-yl)propan-2-one(68 mg). 1-(6-Chloro-2H-indazol-2-yl) propan-2-one was prepared using aprocedure similar to that described in Example 105 part c and d exceptstarting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-2H-indazole that wasprepared as follows:

-   -   a. A mixture of        [2-(tert-butyldimethylsilanyloxy)propyl]-(4-chloro-2-nitrobenzyl)amine        (4.6 g, described in Example 105 part a), and zinc (2 g) in        ethanol (95%, 20 mL) and one drop of acetic acid was heated to        60° C. for 24 hours. The reaction mixture was filtered through a        plug of Celite® and concentrated under reduced pressure to yield        a residue that was purified by chromatography (SiO₂, heptane/EA)        to afford        2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-2H-indazole        as a white solid (0.9 g, 22%) along with recovered starting        material (2.2 g, 48%).

Example 133N-[2-(6-Chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.038)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg,described in Example 132) and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (37 mg, 98%). MS (ES): M/Z[M+H]=439. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s, 3H), 4.81 (d, 1H),4.89 (d, 1H), 7.12 (dd, J=9.0, 1.6 Hz, 1H), 7.65 (d, J=9.0, 1H), 7.69(s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 8.18 (s, 1H)and 8.58 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).

Example 134N-[1-Cyano-2-(4,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.040)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg),the title compound was isolated as a white solid (31 mg, 91%). MS (ES):M/Z [M+H]=457. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.82 (d,1H), 4.92 (d, 1H), 7.15 (d, J=1.3 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.60(s, 1H), 7.89 (d, J=8.8 Hz, 2H) and 8.22 (s, 2H). 19F NMR (376 MHz,CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(4,6-dichloro-2H-indazol-2-yl)-2-methylpropionitrile (88 mg,54%) was prepared using a procedure similar to that described in Example1, part b, except starting from 1-(4,6-dichloro-2H-indazol-2-yl)propan-2-one (146 mg). 1-(4,6-Dichloro-2H-indazol-2-yl)propan-2-one wasprepared using a procedure similar to that described in Example 105 partc and d except starting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-4,6-dichloro-2H-indazole thatwas prepared using a procedure similar to that described in Example 132part a except starting from[2-(tert-butyldimethylsilanyloxy)propyl]-(2,4-dichloro-6-nitrobenzyl)aminedescribed in Example 116.

Example 135N-[1-Cyano-2-(4,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 2.041)

Using a procedure similar to that described in Example 1, except using2-amino-3-(4,6-dichloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg,described in Example 134) and 4-trifluoromethylthiobenzoyl chloride, thetitle compound was isolated as a white solid (34 mg, 97%). MS (ES): M/Z[M+H]=473. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.82 (d, 1H),4.93 (d, 1H), 7.15 (d, J=0.9 Hz, 1H), 7.60 (s, 1H), 7.79 (d, 2H), 7.88(d, 2H), 8.22 (s, 1H) and 8.32 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d):−42.2 (s, 3F).

Example 136N-[1-Cyano-1-methyl-2-(4,6,7-trichloro-2H-indazol-2-yl)ethyl]-4-trifluoromethoxybenzamide(compound No 2.048)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (60mg), the title compound was isolated as a white solid (34 mg, 35%).Rf=0.65 (1:1 EA/heptane). 1H NMR: (400 MHz, DMSO-d₆): 1.70 (s, 3H), 5.12(d, 1H), 5.24 (d, 1H), 7.47 (s, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.97 (d,J=8.8 Hz, 2H), 8.72 (s, 1H) and 8.92 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −57.1 (s, 3F).

2-Amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.16g, 60%) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(4,6,7-trichloro-2H-indazol-2-yl) propan-2-one (0.25 g).1-(4,6,7-Trichloro-2H-indazol-2-yl)propan-2-one was prepared using aprocedure similar to that described in Example 105 part c and d exceptstarting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-4,6,7-trichloro-2H-indazole(1.4 g, 69%) that was prepared using a procedure similar to thatdescribed in Example 132 part a except starting from[2-(tert-butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzyl)amine(2.2 g).[2-(tert-Butyldimethylsilanyloxy)propyl]-(2-nitro-3,4,6-trichlorobenzyl)amine(2.2 g, 44%) was prepared using a procedure similar to that described inExample 105 part a except starting from2-nitro-3,4,6-trichlorobenzaldehyde (3 g) that was prepared as follows:

-   -   a. To a mixture of 2-nitro-3,4,6-trichloroaniline (57 g),        described in Example 39 part a to c, and copper (II) bromide        (105 g) in acetonitrile (1 L) was added tert-butyl nitrite (90%,        37 mL) and the mixture heated to 60° C. overnight. The reaction        mixture was filtered a plug of Celite®, rinsed with ethyl        acetate and the filtrates concentrated under reduced pressure to        yield a residue that was purified by chromatography (SiO₂,        heptane/EA) to afford 2-bromo-3-nitro-1,4,5-trichlorobenzene (53        g, 74%). Rf=0.8 (1:4 EA/heptane).    -   b. 2-Bromo-3-nitro-1,4,5-trichlorobenzene (53 g),        tributylvinyltin (58 mL, 62 g) and        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II),        complex with dichloromethane (1:1) (14 g) were heated in toluene        (400 mL) at 100° C. for 24 hours. The mixture was concentrated        under reduced pressure, taken up in ethyl acetate (1 L) and        treated with a saturated solution of potassium fluoride (300 mL)        overnight. The mixture was filtered through a plug of Celite®,        the organic layer was separated and dried over sodium sulfate,        filtered and concentrated under reduced pressure to give a        residue that was purified by chromatography (SiO₂, heptane/EA)        to afford 3-nitro-1,2,5-trichloro-4-vinylbenzene as an of white        solid (34 g, 78%). Rf=0.75 (1:4 EA/heptane).    -   c. A solution of 3-nitro-1,4,5-trichloro-2-vinylbenzene (27 g)        in a mixture of DCM and methanol (3:1, 300 mL) was treated with        ozone gas for 2 hours at −78° C. The mixture was purged 10        minutes with oxygen and then quenched with dimethyl sulfide (2        mL) at −78° C. The mixture was allowed to warm to 0° C., treated        with a 10% solution of sodium thiosulfate (200 mL) then diluted        with more DCM. The organic layer was collected, dried over        sodium sulfate, filtered and concentrated under reduced pressure        to give a residue that was purified by chromatography (SiO₂,        heptane/EA) to afford 2-nitro-3,4,6-trichlorobenzaldehyde as a        white solid (20 g, 74%). Rf=0.5 (3:8 EA/heptane). 1H NMR: (400        MHz, DMSO-d₆): 8.44 (s, 1H) and 10.17 (s, 1H).

Example 137N-[1-Cyano-1-methyl-2-(4,6,7-trichloro-2H-indazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide(compound No 2.049)

Using a procedure similar to that described in Example 1, except using2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (60mg, described in Example 136) and 4-trifluoromethylthiobenzoyl chloride,the title compound was isolated as a white solid (40 mg, 40%). Rf=0.65(1:1 EA/heptane). 1H NMR: (400 MHz, DMSO-d₆): 1.70 (s, 3H), 5.11 (d,1H), 5.25 (d, 1H), 7.47 (s, 1H), 7.79-7.80 (m, 4H), 8.73 (s, 1H) and9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −42.0 (s, 3F).

Compounds of Examples 138 to 144 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=C—R₈; W=C—H; X=C—R₁₀; Y=C—R₁₁;Q=C—R₂: P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 138N-[1-Cyano-1-methyl-2-(3,6,7-trichloro-2H-indazol-2-yl)ethyl]-4-trifluoromethoxybenzamide(compound No 2.039)

A mixture ofN-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(25 mg, described in Example 132), and N-chlorosuccinimide (50 mg) inacetonitrile (2 mL) was heated to 60° C. overnight. The mixture wasconcentrated under reduced pressure to yield a residue that was purifiedby chromatography (SiO₂, heptane/EA) to afford the title compound (22mg, 75%) with 70% purity along with 30% of another isomer. MS (ES): M/Z[M+H]=491. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.81 (d,J=14.3 Hz, 1H), 5.06 (d, J=14.3 Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 7.32(dd, J=8.1, 0.9 Hz, 2H), 7.51 (d, J=8.9 Hz, 1H), 8.05 (d, J=8.9 Hz, 2H)and 8.92 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

Example 139N-[2-(3-Bromo-6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.042)

A mixture ofN-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(25 mg, described in Example 132), and N-bromosuccinimide (10 mg) inacetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture wascooled to room temperature, diluted with water and extracted with ethylacetate. The organic layer was collected, dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas purified by chromatography (SiO₂, heptane/EA) to afford the titlecompound (12.5 mg, 42%). MS (ES): M/Z [M+H]=501. 1H NMR: (400 MHz,CHLOROFORM-d): 1.90 (s, 3H), 4.82 (d, J=14.3 Hz, 1H), 5.05 (d, J=14.3Hz, 1H), 7.14 (dd, J=9.0, 1.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.50 (d,J=8.9 Hz, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H) and 8.71(s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

Example 140N-[2-(7-Bromo-6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.043)

From the same reaction mixture described in Example 139 was alsoisolated the title compound (5 mg, 17%). MS (ES): M/Z [M+H]=501. 1H NMR:(400 MHz, CHLOROFORM-d): 1.99 (s, 3H), 4.87 (s, 2H), 7.22 (d, J=8.8 Hz,1H), 7.31 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.9 Hz, 1H), 8.04 (d, J=8.8 Hz,2H), 8.31 (s, 1H) and 8.75 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d):−58.1 (s, 3F).

Example 141N-[1-Cyano-2-(3,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.044)

A mixture ofN-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(50 mg, described in Example 132), and N-chlorosuccinimide (16 mg) inacetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture wascooled to room temperature, diluted with water and extracted with ethylacetate. The organic layer was collected, dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas purified by chromatography (SiO₂, heptane/EA) to afford the titlecompound (46 mg, 85%). MS (ES): M/Z [M+H]=457. 1H NMR: (400 MHz,CHLOROFORM-d): 1.92 (s, 3H), 4.80 (d, J=14.3 Hz, 1H), 5.03 (d, J=14.3Hz, 1H), 7.15 (dd, J=9.0, 1.4 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.57 (d,J=9.0 Hz, 1H), 7.63 (s, 1H), 7.93 (d, J=8.7 Hz, 2H) and 8.65 (s, 1H).19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

Example 142N-[1-Cyano-2-(6,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.045)

From the same reaction mixture described in Example 141 was alsoisolated the title compound (6 mg, 11%). MS (ES): M/Z [M+H]=457. 1H NMR:(400 MHz, CHLOROFORM-d): 1.99 (s, 3H), 4.87 (s, 2H), 7.22 (d, J=8.8 Hz,1H), 7.31 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.9 Hz, 1H), 8.02 (d, J=8.8 Hz,2H), 8.26 (s, 1H) and 8.81 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d):−58.1 (s, 3F).

Example 143N-[1-Cyano-2-(3,7-dibromo-4,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.046)

A mixture ofN-[2-(4,6-dichloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide,described in Example 134, and excess N-bromosuccinimide in acetonitrilewas heated to 60° C. overnight. The mixture was cooled to roomtemperature, diluted with water and extracted with ethyl acetate. Theorganic layer was collected, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give a residue that was purifiedby chromatography (SiO₂, heptane/EA) to afford the title compound (13mg). MS (ES): M/Z [M+H]=613. 1H NMR: (400 MHz, CHLOROFORM-d): 1.97 (s,3H), 4.75 (br. s, 1H), 4.88 (d, J=14.3 Hz, 1H), 5.14 (d, J=14.3 Hz, 1H),7.31 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H) and 8.65 (s, 1H). 19F NMR(376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

Example 144N-[2-(7-Bromo-6,7-dichloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.047)

From the same reaction mixture described in Example 143 was alsoisolated the title compound (18 mg). MS (ES): M/Z [M+Na]=557. 1H NMR:(400 MHz, CHLOROFORM-d): 2.00 (s, 3H), 4.84-4.93 (m, 2H), 7.25 (s, 1H),7.31 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 8.35 (s, 1H) and 8.57(s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

The Compound of Example 145 was Prepared According to the FollowingGeneral Reaction Scheme:

Example 145N-[2-(6-Chloro-3-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 2.050)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-methyl-2H-indazol-2-yl)-2-methylpropionitrile (33mg), the title compound was isolated as a white solid (31 mg, 52%). 1HNMR: (400 MHz, CHLOROFORM-d): 1.98 (s, 3H), 2.79 (s, 3H), 4.69 (d, 1H),4.83 (d, 1H), 7.05 (dd, J=8.9, 1.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.55(d, J=9.0 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 2H) and9.19 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-chloro-3-methyl-2H-indazol-2-yl)-2-methylpropionitrile wasprepared using a procedure similar to that described in Example 1, partb, except starting from 1-(6-chloro-3-methyl-2H-indazol-2-yl)propan-2-one. 1-(6-Chloro-3-methyl-2H-indazol-2-yl)propan-2-one wasprepared using a procedure similar to that described in Example 105 partc and d except starting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-3-methyl-2H-indazolethat was prepared as follows:

-   -   a. To a solution of diisopropylamine (0.31 mL) in THF (3 mL) was        added a solution of n-butyl lithium (1.6 molar in hexanes,        1.26 ml) at −78° C. After stirring 30 minutes at −78° C., a        solution of        2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-2H-indazole        (469 g), described in Example 132 part a, in THF (3 mL) was        added and the mixture let warm to −30° C. over one hour. Methyl        iodide (0.126 mL) was added at −30° C. and the mixture let warm        to room temperature and then heated to 50° C. for 24 hours. The        reaction mixture was quenched with water and extracted with        ethyl acetate. The organic layer was collected, dried over        magnesium sulfate, filtered and concentrated under reduced        pressure to yield a residue that was purified by chromatography        (SiO₂, heptane/EA) to afford a mixture (1.3:1, 408 mg) of        desired        2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-3-methyl-2H-indazole        and starting material        2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-2H-indazole.

Compounds of Examples 146 to 149 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=N; W=C—H; X=C—R₁₀; Y=C—R₁₁;Q=C—R₂; P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 146N-[2-(6-Chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.001)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(15 mg), the title compound was isolated as a white solid (24 mg, 82%).MS (ES): M/Z [M+H]=454. 1H NMR: (400 MHz, CHLOROFORM-d): 1.91 (s, 3H),4.52 (d, J=14.2 Hz, 1H), 4.66 (s, 3H), 4.85 (d, J=14.2 Hz, 1H), 7.33 (d,J=8.2 Hz, 2H), 7.77 (d, J=2.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 2H), 8.31 (d,J=2.0 Hz, 1H) and 8.74 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1(s, 3F).

2-Amino-3-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(39 mg) was prepared quantitatively using a procedure similar to thatdescribed in Example 1, part b, except starting from1-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (32mg). 1-(6-Chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-onewas prepared using a procedure similar to that described in Example 105part a to d except using 5-chloro-3-nitropyridine-2-carboxaldehyde (1.2g) and decaborane in part a to yield[2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-3-nitropyridin-2-yl-methyl)amine(0.4 g, 17%). 5-Chloro-3-nitropyridine-2-carboxaldehyde was preparedusing a procedure similar to that described in Example 136 part a to cexcept starting from 2-amino-5-chloro-3-nitropyridine in part a or usingcommercially available 2-bromo-5-chloro-3-nitropyridine in part b.Alternatively, oxidative cleavage using a 4% solution of osmiumtetroxide in water (2 mL) and sodium periodate (1.2 g) was carried outin a mixture of THF and water (10:1, 20 mL) in part c instead ofozonolysis following a procedure similar to that described in Example 61to afford 5-chloro-3-nitropyridine-2-carboxaldehyde (0.72 g, 72%) from5-chloro-3-nitro-2-vinylpyridine (1 g).

Example 147N-[2-(6-Chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 3.002)

Using a procedure similar to that described in Example 1,2-amino-3-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(15 mg, described in Example 146) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (20 mg, 67%).MS (ES): M/Z [M+H]=470. 1H NMR: (400 MHz, CHLOROFORM-d): 1.92 (s, 3H),4.53 (d, J=14.2 Hz, 1H), 4.67 (s, 3H), 4.86 (d, J=14.2 Hz, 1H),7.77-7.82 (m, 3H), 7.93 (d, J=8.2 Hz, 2H), 8.31 (d, J=1.9 Hz, 1H) and8.82 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).

Example 148N-[2-(6-Bromo-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.007)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-bromo-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(20 mg), the title compound was isolated as a white solid (21 mg, 66%).1H NMR: (400 MHz, CHLOROFORM-d): 1.93 (s, 3H), 2.57 (s, 3H), 4.51 (d,J=14.2 Hz, 1H), 4.66 (s, 3H), 4.85 (d, J=14.2 Hz, 1H), 7.31 (d, J=8.3Hz, 2H), 7.97 (d, J=8.7 Hz, 2H), 8.39 (s, 1H) and 9.03 (s, 1H). 19F NMR(376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-bromo-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(20 mg) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(6-bromo-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one(117 mg).1-(6-Bromo-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-onewas prepared using a procedure similar to that described in Example 105part a to d except using5-bromo-4-methyl-3-nitropyridine-2-carboxaldehyde (5.5 g) in part a toyield[2-(tert-butyldimethylsilanyloxy)propyl]-(5-bromo-4-methyl-3-nitropyridin-2-yl-methyl)amine(6 g, 67%). 5-Bromo-4-methyl-3-nitro-pyridine-2-carboxaldehyde wasprepared using a procedure similar to that described in Example 136 parta to c except starting from 2-amino-5-bromo-4-methyl-3-nitropyridine(58.6 g) and using iodine (64 g) in part a instead of copper bromide togenerate 5-bromo-2-iodo-4-methyl-3-nitropyridine (28.7 g, 33%).Oxidative cleavage using a 4% solution of osmium tetroxide in water (3mL) and sodium periodate (23.1 g) was carried out in a mixture of THFand water (10:1, 330 mL) in part c instead of ozonolysis following aprocedure similar to that described in Example 61 to afford5-bromo-4-methyl-3-nitropyridine-2-carboxaldehyde (11.7 g, 59%) from5-bromo-4-methyl-3-nitro-2-vinylpyridine (18.8 g).2-Amino-5-bromo-4-methyl-3-nitropyridine (120.2 g, 85%) was preparedusing a procedure similar to that described in Example 38 part a exceptstarting from 2-amino-4-methyl-3-nitropyridine (101.5 g).

Example 149N-[2-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.008)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(26 mg), the title compound was isolated as a white solid (17 mg, 38%).1H NMR: (400 MHz, CHLOROFORM-d): 1.93 (s, 3H), 2.56 (s, 3H), 4.51 (d,J=14.2 Hz, 1H), 4.66 (s, 3H), 4.86 (d, J=14.2 Hz, 1H), 7.31 (d, J=8.4Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.28 (s, 1H) and 9.05 (s, 1H). 19F NMR(376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(26 mg) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one(78 mg).1-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-onewas prepared using a procedure similar to that described in Example 105part a to d except using5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g) in part a toyield[2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-4-methyl-3-nitropyridin-2-yl-methyl)amine(1.4 g, 57%). 5-Chloro-4-methyl-3-nitro-pyridine-2-carboxaldehyde wasprepared using a procedure similar to that described in Example 136 parta to c except starting from 2-amino-5-chloro-4-methyl-3-nitropyridine(32 g) in part a to generate 2-bromo-5-chloro-4-methyl-3-nitropyridine(25.2 g, 59%). Oxidative cleavage using a 4% solution of osmiumtetroxide in water (1.5 mL) and sodium periodate (2.5 g) was carried outin a mixture of THF and water (10:1, 60 mL) in part c instead ofozonolysis following a procedure similar to that described in Example 61to afford 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g,56%) from 5-chloro-4-methyl-3-nitro-2-vinylpyridine (2.3 g).2-Amino-5-chloro-4-methyl-3-nitropyridine (4.6 g, 75%) was preparedusing a procedure similar to that described in Example 38 part a exceptstarting from 2-amino-4-methyl-3-nitropyridine (5 g) and usingN-chlorosuccinimide (5.8 g) instead of N-bromosuccinimide.

Compounds of Examples 150 to 152 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=N; W=C—H; X=C—R₁₀; Y=C—R₁₁;Q=C—R₂; P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 150N-[2-(6-Bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.009)

Using a procedure adapted from that described in Example 1, using2-amino-3-(6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(27 mg), the title compound was isolated as a white solid (5 mg, 11%).MS (ES): M/Z [M+H]=482. 1H NMR: (400 MHz, CHLOROFORM-d): 1.97 (s, 3H),2.68 (s, 3H), 4.82 (d, 1H), 4.98 (d, 1H), 7.32 (d, J=8.3 Hz, 2H), 7.93(d, J=8.7 Hz, 2H), 8.38 (s, 1H), 8.41 (s, 1H) and 8.61 (s, 1H). 19F NMR(376 MHz, CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(33 mg) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (27 mg).1-(6-Bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one wasprepared using a procedure similar to that described in Example 105 partc and d except starting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridine.2-[2-(tert-Butyldimethylsilanyloxy)propyl]-6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridine(0.15 g, 9%) was isolated along with1-(6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol (0.14 g,12%) using a procedure similar to that described in Example 132 part aexcept using[2-(tert-butyldimethylsilanyloxy)propyl]-(5-bromo-4-methyl-3-nitropyridin-2-yl-methyl)amine(1.9 g) described in Example 148.

Example 151N-[2-(6-Bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 3.023)

Using a procedure adapted from that described in Example 1, using2-amino-3-(6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(56.7 mg, described in Example 150) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (26 mg, 27%).MS (ES): M/Z [M+H]=498. 1H NMR: (400 MHz, CHLOROFORM-d): 1.97 (s, 3H),2.67 (s, 3H), 4.82 (d, 1H), 4.97 (d, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.92(d, J=8.3 Hz, 2H), 8.38 (s, 1H), 8.54 (s, 1H) and 8.61 (s, 1H). 19F NMR(376 MHz, CHLOROFORM-d): −42.3 (s, 3F).

Example 152N-[2-(6-Chloro-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.010)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(32 mg), the title compound was isolated as a white solid (4 mg, 9%). 1HNMR: (400 MHz, CHLOROFORM-d): 1.97 (s, 3H), 2.67 (s, 3H), 4.83 (d, 1H),4.97 (d, 1H), 7.32 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H), 8.39 (s,1H), 8.44 (s, 1H) and 8.51 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d):−58.1 (s, 3F).

2-Amino-3-(6-chloro-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(33 mg) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(6-chloro-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (35mg). 1-(6-Chloro-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-onewas prepared using a procedure similar to that described in Example 105part c and d except starting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-7-methyl-2H-pyrazolo[4,3-b]pyridine.2-[2-(tert-Butyldimethylsilanyloxy)propyl]-6-chloro-7-methyl-2H-pyrazolo[4,3-b]pyridine(0.13 g, 13%) was isolated along with1-(6-chloro-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol (0.13mg, 21%) using a procedure similar to that described in Example 132 parta except using[2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-4-methyl-3-nitropyridin-2-yl-methyl)amine(1.1 g) described in Example 149.

Compounds of Examples 153 to 154 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=N; W=C—H; X=C—R₁₀; =C—R₁₁;Q=P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 153N-[2-(6-Bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.003)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-2-methylpropionitrile(60 mg), the title compound was isolated as a white solid (60 mg, 61%).Rf=0.4 (1:1 EA/heptane). MS (ES): M/Z [M−H]=481. 1H NMR: (400 MHz,DMSO-d₆): 1.76 (s, 3H), 2.56 (s, 3H), 5.41 (d, 1H), 5.54 (d, 1H), 7.52(d, J=8.2 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H) and 8.85 (s, 2H). 19F NMR (376MHz, DMSO-d₆): −57.1 (s, 3F).

2-Amino-3-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-2-methylpropionitrile(0.15 g, 55%) was prepared using a procedure similar to that describedin Example 1, part b, except starting from1-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)propan-2-one(0.25 g) that was prepared as follows:

-   -   a. To a mixture of 2-methyl-2-propen-1-ol (1.4 mL) and        triphenylphosphine (3.7 g) in THF (80 mL) was added dropwise        diisopropyl azodicarboxylate (DIAD, 2.7 mL). After stirring for        15 minutes, 6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine        (2.3 g) was added and the reaction stirred for 3 hours at room        temperature. The mixture was poured into water and extracted        with ethyl acetate and washed with water. The organic layer was        dried over sodium sulfate, filtered and concentrated under        reduced pressure to give a residue that was purified by        chromatography (SiO₂, heptane/EA) to afford        6-bromo-7-methyl-2-(2-methyl-allyl)-2H-[1,2,3]triazolo[4,5-b]pyridine.        6-Bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine (2.4 g, 74%)        was prepared using a procedure similar to that described in        Example 13 part a except starting from        5-bromo-4-methylpyridine-2,3-diamine (3.5 g, 80%) that was        prepared using a procedure similar to that described in Example        38 part b except starting from        2-amino-5-bromo-4-methyl-3-nitropyridine (5 g) described in        Example 148.    -   b. To a solution of        6-bromo-7-methyl-2-(2-methyl-allyl)-2H-[1,2,3]triazolo[4,5-b]pyridine        (0.9 g) in a mixture of THF and water (8:1, 18 mL), was added        sodium periodate (2 g) and a 4% osmium tetroxide solution in        water (2 mL, 5 mole %). After stirring overnight at room        temperature, the mixture was quenched with a 10% solution of        sodium thiosulfate, extracted with ethyl acetate and washed with        water. The organic layer was dried over sodium sulfate, filtered        and concentrated under reduced pressure to give a residue that        was purified by chromatography (SiO₂, heptane/EA) to afford        1-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)propan-2-one        (0.3 g, 33%).

Example 154N-[2-(6-Bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 3.004)

Using a procedure similar to that described in Example 1,2-amino-3-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-2-methylpropionitrile(90 mg, described in Example 153) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (65 mg, 43%).Rf=0.4 (1:1 EA/heptane). MS (ES): M/Z [M−H]=497. 1H NMR: (400 MHz,DMSO-d₆): 1.76 (s, 3H), 2.56 (s, 3H), 5.40 (d, 1H), 5.54 (d, 1H),7.82-7.94 (m, 4H), 8.86 (s, 1H) and 8.93 (s, 1H). 19F NMR (376 MHz,DMSO-d₆): −42.0 (s, 3F).

Compounds of Examples 155 to 158 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=N; W=C—H; X=C—R₁₀; Y=C—R₁₁;Q=C—H; P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 155N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.005)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(1.1 g), the title compound was isolated as a white solid (1 g, 49%). MS(ES): M/Z [M+H]=424. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s, 3H), 4.86(d, J=14.0 Hz, 1H), 5.02 (d, J=14.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H),7.88 (d, J=8.7 Hz, 2H), 8.02 (dd, J=2.1, 0.9 Hz, 1H), 8.03 (s, 1H), 8.42(d, J=0.8 Hz, 1H) and 8.55 (d, J=2.1 Hz, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(1.1 g, 97%) was prepared using a procedure similar to that described inExample 1, part b, except starting from1-(6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (1 g).1-(6-Chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one wasprepared using a procedure similar to that described in Example 105 partc and d except starting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-2H-pyrazolo[4,3-b]pyridinethat was prepared as follows:

-   -   a. To a solution of 5-chloro-3-nitropyridine-2-carboxaldehyde (1        g), described in Example 146, in 1,2-dichloroethane (20 mL) was        added 4 Å molecular sieves powder and        2-(tert-butyldimethylsilanyloxy)propylamine (1.22 g) described        in Example 105 part a. After stirring overnight at room        temperature, sodium cyanoborohydride (0.4 g) and acetic acid        (0.33 mL) were added at 0° C. After stirring for one hour at 0°        C., the reaction mixture was heated to 65° C. overnight. The        reaction mixture was filtered through a plug of Celite® and        concentrated under reduced pressure to yield a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-chloro-2H-pyrazolo[4,3-b]pyridine        (0.6 g, 37%). MS (ES): M/Z [M+H]=326. 1H NMR: (400 MHz,        CHLOROFORM-d): −0.37 (s, 3H), −0.09 (s, 3H), 0.79 (s, 9H), 1.24        (d, J=6.1 Hz, 3H), 4.21-4.31 (m, 1H), 4.33-4.38 (m, 1H),        4.40-4.47 (m, 1H), 8.00 (dd, J=2.1, 0.9 Hz, 1H), 8.22 (d, J=0.7        Hz, 1H) and 8.48 (d, J=2.1 Hz, 1H).

Example 156N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 3.006)

Using a procedure similar to that described in Example 1,2-amino-3-(6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(35 mg, described in Example 155) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (13 mg, 20%).MS (ES): M/Z [M+H]=440. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H),4.86 (d, J=14.0 Hz, 1H), 5.01 (d, J=14.0 Hz, 1H), 7.71-7.83 (m, 2H),7.83-7.92 (m, 2H), 8.02 (dd, J=2.1, 0.9 Hz, 1H), 8.12 (s, 1H), 8.43 (d,J=0.7 Hz, 1H) and 8.56 (d, J=2.1 Hz, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −42.2 (s, 3F).

Example 157N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.011)

Using a procedure similar to that described in Example 1, except using2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(156 mg), the title compound was isolated as a white solid (133 mg,48%). MS (ES): M/Z [M+H]=468. 1H NMR: (400 MHz, CHLOROFORM-d): 1.93 (s,3H), 4.84 (d, J=14.0 Hz, 1H), 5.00 (d, J=14.1 Hz, 1H), 7.31 (d, J=8.1Hz, 2H), 7.82-7.90 (m, 2H), 7.99 (s, 1H), 8.20 (dd, J=1.9, 0.8 Hz, 1H),8.39 (s, 1H) and 8.61 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −58.1 (s, 3F).

2-Amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(416 mg, 80%) was prepared using a procedure similar to that describedin Example 1, part b, except starting from1-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (471 mg).1-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was preparedusing a procedure similar to that described in Example 105 part c and dexcept starting from2-[2-(tert-butyldimethylsilanyloxy)propyl]-6-bromo-2H-pyrazolo[4,3-b]pyridine(289 mg, 39%) that was prepared using a procedure similar to thatdescribed in Example 155 except starting from5-bromo-3-nitropyridine-2-carboxaldehyde (462 mg).5-Bromo-3-nitropyridine-2-carboxaldehyde was prepared using a proceduresimilar to that described in Example 136 part a to c except startingfrom 2-amino-5-bromo-3-nitropyridine (50 g) and using iodine (69.9 g) inpart a instead of copper bromide to generate5-bromo-2-iodo-3-nitropyridine as a yellow solid (27.4 g, 36%).Oxidative cleavage using a 4% solution of osmium tetroxide in water (4mL) and sodium periodate (6.7 g) was carried out in a mixture of THF andwater (10:1, 390 mL) in part c instead of ozonolysis following aprocedure similar to that described in Example 61 to afford5-bromo-3-nitropyridine-2-carboxaldehyde as a tan solid (3.8 g, 62%)from 5-bromo-3-nitro-2-vinylpyridine (6 g).

Example 158N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide(compound No 3.012)

Using a procedure similar to that described in Example 1,2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile(223 mg described in Example 157) and 4-trifluoromethylthiobenzoylchloride, the title compound was isolated as a white solid (145 mg,38%). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s,3H), 4.86 (d, J=14.0 Hz, 1H), 5.01 (d, J=14.1 Hz, 1H), 7.78 (d, J=8.3Hz, 2H), 7.84-7.90 (m, 2H), 8.11 (s, 1H), 8.22 (dd, J=2.0, 1.0 Hz, 1H),8.42 (d, J=0.8 Hz, 1H) and 8.64 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz,CHLOROFORM-d): −42.2 (s, 3F).

Compounds of Examples 159 to 160 were Prepared According to theFollowing General Reaction Scheme

Final ProductV=N; W=C—H; X=C—R₁₀; Y=C—R₁₁;Q=C—R₂; P=N;R₃=R₄=H; a=1; R₅=CH₃, R₆=H;Z=C(O); R₇=p-phenyl-R

Example 159N-[1-Cyano-2-(3,6-dichloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.017)

A mixture ofN-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(134 mg described in Example 155), and N-chlorosuccinimide (51 mg) inacetonitrile (3.5 mL) was heated to 60° C. overnight. The mixture wasconcentrated under reduced pressure to yield a residue that was purifiedby chromatography (SiO₂, heptane/EA) to afford the title compound aswhite solid (129 mg, 89%). MS (ES): M/Z [M+H]=458. 1H NMR: (400 MHz,DMSO-d₆): 1.78 (s, 3H), 5.10-5.20 (m, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.97(d, J=8.8 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H) and8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

Example 160N-[2-(3-Bromo-6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(compound No 3.019)

A mixture ofN-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide(134 mg described in Example 155) and N-bromosuccinimide (68 mg) inacetonitrile (3.5 mL) was heated to 60° C. overnight. The mixture wasconcentrated under reduced pressure to yield a residue that was purifiedby chromatography (SiO₂, heptane/EA) to afford the title compound as awhite solid (125 mg, 80%). MS (ES): M/Z [M+H]=502. 1H NMR: (400 MHz,DMSO-d₆): 1.78 (s, 3H), 5.10-5.22 (m, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.98(d, J=8.7 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.58 (d, J=1.9 Hz, 1H) and9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d₆): −57.1 (s, 3F).

TABLE 1 (Ic)

Com- pound # R R₅ R₈ R₉ R₁₀ R₁₁ 1.001 OCF₃ Me H Cl H H 1.002 CF₃ Me H ClH H 1.003 SCF₃ Me H Cl H H 1.004 OCF₃ Me H H H H 1.005 SCF₃ Me H H H H1.006 OCF₃ Me H Me H H 1.007 SCF₃ Me H Me H H 1.008 OCF₃ Me H CF₃ H H1.009 SCF₃ Me H CF₃ H H 1.010 OCF₃ Me H Cl Cl H 1.011 SCF₃ Me H Cl Cl H1.012 OCF₃ Me Cl H Cl H 1.013 SCF₃ Me Cl H Cl H 1.014 OCF₃ Me Cl H CF₃ H1.015 SCF₃ Me Cl H CF₃ H 1.016 OCF₃ Me H CN H H 1.017 SCF₃ Me H CN H H1.018 OCF₃ Me CF₃ H CF₃ H 1.019 SCF₃ Me CF₃ H CF₃ H 1.020 OCF₃ Me H Br HH 1.021 SCF₃ Me H Br H H 1.022 SOCF₃ Me H CN H H 1.023 SOCF₃ Me Cl H CF₃H 1.024 SOCF₃ Me Cl H Cl H 1.025 SO₂CF₃ Me Cl H Cl H 1.026 SO₂CF₃ Me HCF₃ H H 1.027 SO₂CF₃ Me H CN H H 1.028 SO₂CF₃ Me Cl H CF₃ H 1.029 SO₂CF₃Me H H H H 1.030 SO₂CF₃ Me H Me H H 1.031 SO₂CF₃ Me H Cl H H 1.032 OPhMe H Cl H H 1.033 OCF₃ Me Me H Cl H 1.034 SCF₃ Me Me H Cl H 1.035 OCF₃Me H OCF₃ H H 1.036 SCF₃ Me H OCF₃ H H 1.037 OCF₃ Me CF₃ H Cl H 1.038SCF₃ Me CF₃ H Cl H 1.039 OPh Me Me H Cl H 1.040 OCF₃ Me H Cl Me H 1.041SCF₃ Me H Cl Me H 1.042 OPh Me CF₃ H Cl H 1.043 OCF₃ Me Cl H H H 1.044SCF₃ Me Cl H H H 1.045 OPh Me Cl H H H 1.046 Ph Me Cl H Cl H 1.047 OCF₃Et H Cl H H 1.048 SCF₃ Et H Cl H H 1.049 OCF₃ CH₂CH(CH₃)₂ H Cl H H 1.050SCF₃ CH₂CH(CH₃)₂ H Cl H H 1.051 OCF₃ t-Bu H Cl H H 1.052 SCF₃ t-Bu H ClH H 1.053 t-Bu Me Cl H Cl H 1.054 OCF₃ Me CN H CF₃ H 1.055 SCF₃ Me CN HCF₃ H 1.056 OCF₃ Me CF₃ H CN H 1.057 OCF₃ Me Br Cl H H 1.058 OCF₃ CH₂OHH Cl H H 1.059 SCF₃ CH₂OH H Cl H H 1.060 OCF₃ Me Br H Cl H 1.061 OCF₃CH₂SMe H Cl H H 1.062 OCF₃ CH₂OMe H Cl H H 1.063 OCF₃ CHOSO₂Me H Cl H H1.064 OCF₃ Me Cl Cl H Cl 1.065 SCF₃ Me Cl Cl H Cl 1.066 SCF₃ Me CF₃ H CNH 1.067 OCF₃ Me CN H Cl H 1.068 OCF₃ Me p-Ph—CF₃ H Cl H 1.069 CHFCF₃ MeCl Cl H Cl 1.070 OCF₃ Me Cl H OMe H 1.071 SCF₃ Me Cl H OMe H 1.072 OCF₃Me H OMe H H 1.073 SCF₃ Me H OMe H H 1.074 OCF₃ Me CH₂NH₂ H Cl H 1.075OCF₃ Me Vinyl H Cl H 1.076 SCF₃ Me Vinyl H Cl H 1.077 OCF₃ MeCH(OH)CH₂OH H Cl H 1.078 OCF₃ Me CH(F)CH₂F H Cl H 1.079 OCF₃ Me Formyl HCl H 1.080 OCF₃ Me CH₂NMe₂ H Cl H 1.081 OCF₃ Me CH₂OH H Cl H 1.082 OCF₃Me CO₂H H Cl H 1.083 OCF₃ Me Br Cl H Br 1.084 OCF₃ Me CO₂Me H Cl H 1.085SCF₃ Me Br Cl H Br 1.086 OCF₃ Me Br Cl H Cl 1.087 SCF₃ Me Br Cl H Cl1.088 OCF₃ Me Br Cl Br Cl 1.089 SCF₃ Me Br Cl Br Cl 1.090 OCF₃ Me F Cl HCl 1.091 SCF₃ Me F Cl H Cl 1.092 OCF₃ Me Me Cl H Me 1.093 SCF₃ Me Me ClH Me 1.094 OCF₃ Me F Br H Me 1.095 SCF₃ Me F Br H MeCompounds of General Formula (Ic) which are of Particular Interest are:

-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.001)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylbenzamide    (compound No 1.002)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.003)-   N-[2-(2H-Benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.004)-   N-[2-(2H-Benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.005)-   N-[1-Cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethoxybenzamide    (compound No 1.006)-   N-[1-Cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide    (compound No 1.007)-   N-[1-Cyano-1-methyl-2-(5-trifluoromethyl-2-yl)-benzotriazol-2-ylethyl]-4-trifluoromethoxybenzamide    (compound No 1.008)-   N-[1-Cyano-1-methyl-2-(5-trifluoromethyl-2-yl)-benzotriazol-2-ylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.009)-   N-[1-Cyano-2-(5,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.010)-   N-[1-Cyano-2-(5,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.011)-   N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.012)-   N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.013)-   N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.014)-   N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.015)-   N-[1-Cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.016)-   N-[1-Cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.017)-   N-[2-(4,6-Bis(trifluoromethyl)-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.018)-   N-[2-(4,6-Bis(trifluoromethyl)-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.019)-   N-[2-(5-Bromo-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.020)-   N-[2-(5-Bromo-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.021)-   N-[1-Cyano-2-(5-cyano-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylsulfinylbenzamide    (compound No 1.022)-   N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfinylbenzamide    (compound No 1.023)-   N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylsulfinylbenzamide    (compound No 1.024)-   N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylsulfonylbenzamide    (compound No 1.025)-   N-[1-Cyano-1-methyl-2-(5-trifluoromethyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylsulfonylbenzamide    (compound No 1.026)-   N-[1-Cyano-1-methyl-2-(5-cyano-2H-benzotriazol-2-yl)-ethyl]-4-trifluoromethylsulfonylbenzamide    (compound No 1.027)-   N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfonylbenzamide    (compound No 1.028)-   N-[2-(2H-Benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfonylbenzamide    (compound No 1.029)-   N-[1-Cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylsulfonylbenzamide    (compound No 1.030)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylsulfonylbenzamide    (compound No 1.031)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide    (compound No 1.032)-   N-[2-(6-Chloro-4-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.033)-   N-[2-(6-Chloro-4-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.034)-   N-[1-Cyano-1-methyl-2-(5-trifluoromethoxy-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethoxybenzamide    (compound No 1.035)-   N-[1-Cyano-1-methyl-2-(5-trifluoromethoxy-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide    (compound No 1.036)-   N-[2-(6-Chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.037)-   N-[2-(6-Chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.038)-   N-[2-(6-Chloro-4-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide    (compound No 1.039)-   N-[2-(5-Chloro-6-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.040)-   N-[1-Cyano-1-methyl-2-(5-methyl-2H-benzotriazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide    (compound No 1.041)-   N-[2-(6-Chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide    (compound No 1.042)-   N-[2-(4-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.043)-   N-[2-(4-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.044)-   N-[2-(4-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-phenoxybenzamide    (compound No 1.045)-   N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]biphenyl-4-carboxamide    (compound No 1.046)-   N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyanopropyl}-4-trifluoromethoxybenzamide    (compound No 1.047)-   N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyanopropyl}-4-trifluoromethylthiobenzamide    (compound No 1.048)-   N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-3-methylbutyl}-4-trifluoromethoxybenzamide    (compound No 1.049)-   N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-3-methylbutyl}-4-trifluoromethylthiobenzamide    (compound No 1.050)-   N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-2,2-dimethylpropyl}-4-trifluoromethoxybenzamide    (compound No 1.051)-   N-{1-[(5-Chloro-2H-benzotriazol-2-yl)methyl]-1-cyano-2,2-dimethylpropyl}-4-trifluoromethylthiobenzamide    (compound No 1.052)-   N-[1-Cyano-2-(4,6-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-tert-butylbenzamide    (compound No 1.053)-   N-[1-Cyano-2-(4-cyano-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.054)-   N-[1-Cyano-2-(4-cyano-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.055)-   N-[1-Cyano-2-(6-cyano-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.056)-   N-[2-(4-Bromo-5-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.057)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(hydroxymethyl)ethyl]-4-trifluoromethoxybenzamide    (compound No 1.058)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(hydroxymethyl)ethyl]-4-trifluoromethylthiobenzamide    (compound No 1.059)-   N-[2-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.060)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(methylthiomethyl)ethyl]-4-trifluoromethoxybenzamide    (compound No 1.061)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(methoxymethyl)ethyl]-4-trifluoromethoxybenzamide    (compound No 1.062)-   N-[2-(5-Chloro-2H-benzotriazol-2-yl)-1-cyano-1-(methanesulfonylmethyl)ethyl]-4-trifluoromethoxybenzamide    (compound No 1.063)-   N-[1-Cyano-1-methyl-2-(4,5,7-trichloro-2H-benzotriazol-2-yl)-ethyl]-4-trifluoromethoxybenzamide    (compound No 1.064)-   N-[1-Cyano-1-methyl-2-(4,5,7-trichloro-2H-benzotriazol-2-yl)-ethyl]-4-trifluoromethylthiobenzamide    (compound No 1.065)-   N-[1-Cyano-2-(6-cyano-4-trifluoromethyl-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.066)-   N-[2-(6-Chloro-4-cyano-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.067)-   N-{2-[6-Chloro-4-(4-trifluoromethylphenyl)-2H-benzotriazol-2-yl]-1-cyano-1-methylethyl}-4-trifluoromethoxybenzamide    (compound No 1.068)-   N-[1-Cyano-1-methyl-2-(4,5,7-trichloro-2H-benzotriazol-2-yl)-ethyl]-4-(1,2,2,2-tetrafluoroethyl)benzamide    (compound No 1.069)-   N-[2-(4-Chloro-6-methoxy-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.070)-   N-[2-(4-Chloro-6-methoxy-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.071)-   N-[1-cyano-2-(5-methoxy-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.072)-   N-[1-cyano-2-(5-methoxy-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.073)-   N-[2-(4-Aminomethyl-6-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.074)-   N-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.075)-   N-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.076)-   N-{2-[6-Chloro-4-(1,2-dihydroxyethyl)-2H-benzotriazol-2-yl]-1-cyano-1-methyl-ethyl}-4-trifluoromethoxybenzamide    (compound No 1.077)-   N-{2-[6-Chloro-4-(1,2-difluoroethyl)-2H-benzotriazol-2-yl]-1-cyano-1-methyl-ethyl}-4-trifluoromethoxybenzamide    (compound No 1.078)-   N-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.079)-   N-[2-(6-Chloro-4-dimethylaminomethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.080)-   N-[2-(6-Chloro-4-hydroxymethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.081)-   6-Chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}amino)-propyl]-2H-benzotriazole-4-carboxylic    acid (compound No 1.082)-   Methyl    6-chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}-amino)propyl]-2H-benzotriazole-4-carboxylate    (compound No 1.084)-   N-[2-(5-Chloro-4,7-dibromo-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.085)-   N-[2-(4-Bromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.086)-   N-[2-(4-Bromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.087)-   N-[1-Cyano-2-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.088)-   N-[1-Cyano-2-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.089)-   N-[1-Cyano-2-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.090)-   N-[1-Cyano-2-(5,7-dichloro-4-fluoro-2H-benzotriazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.091)-   N-[2-(5-Chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.092)-   N-[2-(5-Chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.093)-   N-[2-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 1.094)-   N-[2-(5-bromo-4-fluoro-7-methyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 1.095)

The numbers 1.001 to 1.095 are assigned to the above compounds foridentification and reference hereinafter.

TABLE 2 (Id)

Compound # R R₂ R₈ R₉ R₁₀ R₁₁ 2.001 OCF₃ H H NO₂ H H 2.002 SCF₃ H H NO₂H H 2.003 OCF₃ H H Cl H Cl 2.004 OPh H H Cl H Cl 2.005 SCF₃ H H Cl H Cl2.006 OCF₃ H H Cl H Me 2.007 SCF₃ H H Cl H Me 2.008 OCF₃ OMe H H Cl H2.009 SCF₃ OMe H H Cl H 2.010 OCF₃ Me H Cl H Cl 2.011 SCF₃ Me H Cl H Cl2.012 OCF₃ OMe H Cl H H 2.013 SCF₃ OMe H Cl H H 2.014 OCF₃ OEt H Cl H H2.015 SCF₃ OEt H Cl H H 2.016 OCF₃ OMe H H H H 2.017 OCF₃ O(CH₂)₂OMe H HCl H 2.018 OCF₃ O(CH₂)₂NMe₂ H H Cl H 2.019 SCF₃ OMe H Cl H Cl 2.020 OCF₃OMe H Cl H Cl 2.021 OCF₃ OMe Cl H Cl H 2.022 SCF₃ OMe Cl H Cl H 2.023OCF₃ OMe H H Br H 2.024 SCF₃ OMe H H Br H 2.025 OCF₃ OMe H H CF₃ H 2.026SCF₃ OMe H H CF₃ H 2.027 OCF₃ OEt H H Cl H 2.028 SCF₃ OEt H H Cl H 2.029OCF₃ O—n-Pr H H Cl H 2.030 SCF₃ O—n-Pr H H Cl H 2.031 OCF₃ O—n-Bu H H ClH 2.032 OCF₃ OMe H H CO₂Me H 2.033 OCF₃ OMe H H NO₂ H 2.034 OCF₃ OMe H HNH₂ H 2.035 OCF₃ OMe H H NHAc H 2.036 OCF₃ OMe H H CONH₂ H 2.037 OCF₃ HH H Cl H 2.038 SCF₃ H H H Cl H 2.039 OCF₃ Cl H H Cl Cl 2.040 OCF₃ H Cl HCl H 2.041 SCF₃ H Cl H Cl H 2.042 OCF₃ Br H H Cl H 2.043 OCF₃ H H H ClBr 2.044 OCF₃ Cl H H Cl H 2.045 OCF₃ H H H Cl Cl 2.046 OCF₃ Br Cl H ClBr 2.047 OCF₃ H Cl H Cl Br 2.048 OCF₃ H Cl H Cl Cl 2.049 SCF₃ H Cl H ClCl 2.050 OCF₃ Me H H Cl HCompounds of General Formula (Id) which are of Particular Interest are:

-   N-[1-Cyano-1-methyl-2-(5-nitro-2H-indazol-2-yl)ethyl]-4-trifluoromethoxybenzamide    (compound No 2.001)-   N-[1-Cyano-1-methyl-2-(5-nitro-2H-indazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide    (compound No 2.002)-   N-[1-Cyano-2-(5,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.003)-   N-[1-Cyano-2-(5,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-phenoxybenzamide    (compound No 2.004)-   N-[1-Cyano-2-(5,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.005)-   N-[2-(5-Chloro-7-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.006)-   N-[2-(5-Chloro-7-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.007)-   N-[2-(6-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.008)-   N-[2-(6-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.009)-   N-[1-Cyano-2-(5,7-dichloro-3-methyl-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.010)-   N-[2-(5,7-Dichloro-3-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.011)-   N-[2-(5-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.012)-   N-[2-(5-Chloro-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.013)-   N-[2-(5-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.014)-   N-[2-(5-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.015)-   N-[1-Cyano-2-(3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.016)-   N-{2-[6-Chloro-3-(2-methoxyethoxy)-2H-indazol-2-yl]-1-cyano-1-methylethyl}-4-trifluoromethoxybenzamide    (compound No 2.017)-   N-{2-[6-Chloro-3-(2-dimethylaminoethoxy)-2H-indazol-2-yl]-1-cyano-1-methylethyl}-4-trifluoromethoxybenzamide    (compound No 2.018)-   N-[1-Cyano-2-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.019)-   N-[1-Cyano-2-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.020)-   N-[1-Cyano-2-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.021)-   N-[1-Cyano-2-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.022)-   N-[2-(6-Bromo-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.023)-   N-[2-(6-Bromo-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.024)-   N-[1-Cyano-2-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.025)-   N-[1-Cyano-2-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.026)-   N-[2-(6-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.027)-   N-[2-(6-Chloro-3-ethoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.028)-   N-[2-(6-Chloro-3-propoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.029)-   N-[2-(6-Chloro-3-propoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.030)-   N-[2-(6-Chloro-3-butoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.031)-   Methyl    2-[2-cyano-2-methyl-2-(4-trifluoromethoxybenzoylamino)ethyl]-3-methoxy-2H-indazole-6-carboxylate    (compound No 2.032)-   N-[1-Cyano-2-(3-methoxy-6-nitro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.033)-   N-[2-(6-Amino-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.034)-   N-[2-(6-Acetylamino-3-methoxy-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.035)-   Methyl    2-[2-cyano-2-methyl-2-(4-trifluoromethoxybenzoylamino)ethyl]-3-methoxy-2H-indazole-6-carboxamide    (compound No 2.036)-   N-[2-(6-Chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.037)-   N-[2-(6-Chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.038)-   N-[1-Cyano-1-methyl-2-(3,6,7-trichloro-2H-indazol-2-yl)ethyl]-4-trifluoromethoxybenzamide    (compound No 2.039)-   N-[1-Cyano-2-(4,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.040)-   N-[1-Cyano-2-(4,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 2.041)-   N-[2-(3-Bromo-6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.042)-   N-[2-(7-Bromo-6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.043)-   N-[1-Cyano-2-(3,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.044)-   N-[1-Cyano-2-(6,7-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.045)-   N-[1-Cyano-2-(3,7-dibromo-4,6-dichloro-2H-indazol-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.046)-   N-[2-(7-Bromo-6,7-dichloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.047)-   N-[1-Cyano-1-methyl-2-(4,6,7-trichloro-2H-indazol-2-yl)ethyl]-4-trifluoromethoxybenzamide    (compound No 2.048)-   N-[1-Cyano-1-methyl-2-(4,6,7-trichloro-2H-indazol-2-yl)ethyl]-4-trifluoromethylthiobenzamide    (compound No 2.049)-   N-[2-(6-Chloro-3-methyl-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 2.050)

The numbers 2.001 to 2.050 are assigned to the above compounds foridentification and reference hereinafter.

TABLE 3 (Ie)

Compound # R Q R₉ R₁₀ R₁₁ 3.001 OCF₃ C—OMe H Cl H 3.002 SCF₃ C—OMe H ClH 3.003 OCF₃ N H Br Me 3.004 SCF₃ N H Br Me 3.005 OCF₃ C—H H Cl H 3.006SCF₃ C—H H Cl H 3.007 OCF₃ C—OMe H Br Me 3.008 OCF₃ C—OMe H Cl Me 3.009OCF₃ C—H H Br Me 3.010 OCF₃ C—H H Cl Me 3.011 OCF₃ C—H H Br H 3.012 SCF₃C—H H Br H 3.013 OCF₃ C—H H Cl Cl 3.014 SCF₃ C—H H Cl Cl 3.015 OCF₃ C—HH Br Cl 3.016 SCF₃ C—H H Br Cl 3.017 OCF₃ C—Cl H Cl H 3.018 SCF₃ C—Cl HCl H 3.019 OCF₃ C—Br H Cl H 3.020 SCF₃ C—Br H Cl H 3.021 OCF₃ C—H H ClBr 3.022 SCF₃ C—H H Cl Br 3.023 SCF₃ C—H H Br MeCompounds of General Formula (Ie) which are of Particular Interest are:

-   N-[2-(6-Chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.001)-   N-[2-(6-Chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 3.002)-   N-[2-(6-Bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.003)-   N-[2-(6-Bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 3.004)-   N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.005)-   N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 3.006)-   N-[2-(6-Bromo-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.007)-   N-[2-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.008)-   N-[2-(6-Bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.009)-   N-[2-(6-Chloro-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.010)-   N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.011)-   N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 3.012)-   N-[2-(6-Bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethylthiobenzamide    (compound No 3.023)-   N-[1-Cyano-2-(3,6-dichloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.017)-   N-[2-(3-Bromo-6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide    (compound No 3.019)

The numbers 3.001 to 3.012, 3.017, 3019 and 3.023 are assigned to theabove compounds for identification and reference hereinafter.

Method of Use Examples

Method A: Screening Method to Test Activity of Compounds AgainstHaemonchus contortus.

Twenty L1 Haemonchus contortus larvae were added to wells of amicrotitre plate containing a nutrient medium and the test compound inDMSO. The microtitre plate was then held at 27° C. where the L1 larvaewere allowed to develop. An analysis was conducted at 4 days todetermine successful development to the L3 stage. Larvae exposed to DMSOand no test compound served as controls. Compounds numbers 1.002, 1.005,1.006, 1.008, 1.009, 1.010, 1.011, 1.014, 1.017, 1.018, 1.025, 1.031,1.045, 1.054, 1.055, 1.061, 1.076, 1.079, 1.081, 1.084, 2.004, 2.010,2.020, 2.033, 3.003 and 3.004 gave at least 90% motility inhibition at atest concentration of 0.15 ppm at the 4 days assessment. Compoundsnumbers 1.003, 1.007, 1.011, 1.015, 1.032, 1.038, 1.042, 1.043, 1.047,1.048, 1.056, 1.057, 1.060, 1.066, 1.067, 1.070, 1.071, 1.075, 1.078,2.001, 2002, 2.003, 2.005, 2.006, 2.007, 2.013, 2.015, 2.016, 2.021,3010 and 3.019 gave at least 90% motility inhibition at a testconcentration of 0.04 ppm at the 4 days assessment. Compounds numbers1.001, 1.012, 1.020, 1.021, 1.033, 1.034, 1.037, 1.039, 1.044, 1.085,1.089, 1.091, 1.092, 1.093, 2.012, 2.014, 2.027, 2.028, 2.039, 3.005,3.007, 3.008 and 3.017 gave at least 90% motility inhibition at a testconcentration of 0.01 ppm at the 4 days assessment. Compounds numbers1.064, 1.065, 1.069, 1.083, 1.086, 1.087, 1.088, 1.090, 1.094, 1.095,2.008, 2.009, 2.023, 2.024, 2.025, 2.026, 2.037, 2.038, 2.040, 2.041,2.042, 2.043, 2.044, 2.045, 2.046, 2.047, 2.048, 2.049, 2.050, 3.001,3.002, 3.006, 3.009, 3.011, 3.012 and 3.023 gave at least 90% motilityinhibition at a test concentration of 0.0025 ppm at the 4 daysassessment.

Method B: Screening Method to Test Activity of Compounds AgainstHaemonchus contortus In Vivo in Mongolian Gerbil (Merionesunguiculatus).

Mongolian gerbils, at least five weeks old, were immunosuppressed andartificially infected with ca. 1000 ensheathed Haemonchus contortusthird instar larvae. Six days after infection, the Mongolian gerbilswere treated by oral gavage with the test compounds, dissolved in amixture of 2 parts DMSO and 1 part polyethylene glycol (PEG400), atdoses of 100 mg/kg and dissolved in pure polyethylene glycol (PEG400) atdoses of 10 and 1 mg/kg. Jirds treated only with the placebo (2 partsDMSO and 1 part PEG400 or pure PEG400) served as controls. On day 9 (3days after treatment) the jirds were euthanized and necropsied forrecovery of parasites from the stomach. Efficacy was calculated as theaverage % reduction in the number of worms in each test group comparedwith the average number of worms from the control group. In this screen,a vast reduction in nematode infestation was achieved with compounds offormula (I), especially from table 1, 2 and 3. Compound numbers 1.001,1.008, 1.012, 1.013 and 1.014 provided at least 95% reduction innematode infestation in Mongolian gerbils treated by oral gavage withtest article at a dose of 100 mg/kg. Compound numbers 1.012, 1.033,1.064, 2.008, 2.037, 2.038, 2.040, 2.041, 3.001 provided at least 95%reduction in nematode infestation at a dose of 10 mg/kg. Compoundnumbers 1.094, 2.048, 3.001, 3.007 and 3.009, provided at least 95%reduction in nematode infestation at a dose of 1 mg/kg. Compound numbers3.005, 3.006, 3.011, 3.012, 3.017 and 3.019, provided at least 95%reduction in nematode infestation at a dose of 0.5 mg/kg.

Method C: Screening Method to Test Activity of Compounds AgainstCtenocephalides felis.

Three to five day old Ctenocephalides felis adults (50) were aspiratedinto a test cage. A separate glass cylinder closed on one end with aself-sealing flexible film was placed on top of the test cage in such aposition that the fleas could pierce the film and feed on the contentsof the glass cylinder. The test compound was dissolved in DMSO and addedto bovine blood which was then placed in the glass cylinder. DMSOtreated blood served as the control. The fleas were held at 20-22° C.,40-60% relative humidity while the treated blood was held at 37° C. and40-60% relative humidity. The treated blood was changed daily for sixdays during which time eggs and fecal material were allowed toaccumulate in the flea cage. On day 6, the contents of each cage wereinspected and placed in a dish containing larval diet consisting ofsand, ground cat food and dried cow blood. The dishes were held at 28°C. and 82% relative humidity 11 days. Pupae were then sieved, weighedand returned to the controlled conditions for an additional 5 days afterwhich adult emergence was assessed. Pupal weights and adult emergencewere then compared to the controls. Compounds numbers 1.012, 1.013,1.020, 1.034, 1.064 and 3.005 gave at least 80% reduction in pupalweights at a test concentration of 100 ppm. Compounds numbers 2.048 gaveat least 80% reduction in pupal weights at a test concentration of 25ppm.

Method D: Screening Method to Test Activity of Compounds AgainstTrichostrongylusl colubriformis.

Twenty L1 Trichostrongylus colubriformis larvae were added to wells of amicrotitre plate containing a nutrient medium and the test compound inDMSO. The microtitre plate was then held at 27° C. where the L1 larvaewere allowed to develop. An analysis was conducted at 4 days todetermine successful development to the L3 stage. Larvae exposed to DMSOand no test compound served as controls. Compounds numbers 1.008, 1.014,1.042, 1.047, 1.048, 1.073, 2.001, 2.003 and 2.020, gave at least 90%motility inhibition at a test concentration of 0.15 ppm at the 4 daysassessment. Compounds numbers 1.001, 1.003, 1.007, 1.011, 1.037, 1.038,1.043, 1.056, 1.066, 1.070, 1.071, 2.012 and 2.016, gave at least 90%motility inhibition at a test concentration of 0.04 ppm at the 4 daysassessment. Compounds numbers 1.012, 1.020, 1.021, 1.033, 1.034, 1.039,1.064, 1.065, 2,008, 2.009 and 3.005 gave at least 90% motilityinhibition at a test concentration of 0.01 ppm at the 4 days assessment.Compounds numbers 1.094, 2.040, 2.048, 2.049, 3.006, 3.009, 3.011 and3.012 gave at least 90% motility inhibition at a test concentration of0.0025 ppm at the 4 days assessment.

Method E: Screening Method to Test Activity of Compounds AgainstHaemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei,Trichostrongylus colubriformis, Cooperia curticei and Nematodirus battusIn Vivo in Sheep.

Sheep were challenged orally with infective 3^(rd) stage larvae (L3) ofOstertagia circumcincta (3,000 infective L3 per animal) on Day −28,Haemonchus contortus (˜2,000 infective L3 per animal) on Day −25,Nematodirus battus (˜3,000 infective L3 per animal) and Trichostrongylusaxei (˜3,000 infective L3 per animal) on Day −23 and Cooperia curticei(˜3,000 infective L3 per animal) and Trichostrongylus colubriformis(˜3,000 infective L3 per species per animal) on Day −21. The inoculationschedule was designed so that nematodes were expected to be in the adultstage on Day 0. Test compounds were dissolved in a mixture of DMSO/Cornoil (1:1) at a concentration of 100 mg/mL. All treatments wereadministered orally once on Day 0. At sacrifice on Day 15 the abomasum,small intestine and large intestine (including cecum) were removed.Nematode counts were conducted on 10% (abomasal and small intestinalcontent, abomasal soak) or 20% aliquots (large intestinal content). Allnematodes were speciated, or assigned to species based on location ofrecovery (adult females, fourth-stage larvae) for a total count perspecies. Efficacy was calculated as the % reduction in the mean numberof worms in each test group compared with the mean number of wormsrecovered from the control group. In this screen, a significantreduction in nematode infestation was achieved with compounds of formula(I), especially from table 1, 2 and 3. Compound numbers 1.012 and 1.013provided at least 90% reduction in nematode infestation at a dose of 30mg/kg.

In addition, compound numbers 1.064, 1.094, 2.048, 3.005, 3.009 and3.011 provided >90% efficacy against one or more species of thenematodes tested, at doses as low as 1 or 3 mg/kg. For example, compound3.009 provided >95% efficacy against Trichostrongylus at a dose of 3mg/kg and compound numbers 1.064, 1.094 and 2.048 provided >95% efficacyagainst Haemonchus, Ostertagia, and Trichostrongylus at a dose of 3mg/kg, and compound numbers 3.005 and 3.011 were more than 95% effectiveagainst these parasites at doses as low as 1 mg/kg.

Method F: Screening Method to Test Activity of Compounds AgainstMicrofilaria of Dirofilaria immitis.

Four hundred to six hundred microfilaria of Dirofilaria immitis wereadded to wells of a microtitre plate containing buffer and the testcompound in DMSO. The microtitre plate was then held at 37° C. in anenvironment containing 5% CO₂. An assessment was conducted at 24 hoursto determine survival of the microfilaria. Microfilaria exposed to DMSOand no test compound served as controls. Compounds numbers 1.003, 1.012,1.013, 1.064, 1.086, 1.087, 1.090, 1.094, 2.043, 2.046, 2.047, 2.048,2.049, 3.005, 3.006, 3.009, 3.011, 3.012, 3.017, 3.019 and 3.023 gave atleast 90% motility inhibition at a test concentration of 50 ppm.

Having thus described in detail various embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

The invention claimed is:
 1. An aryloazol-2-yl-cyanoethylamine compoundof the formula (I):

P is N; Q is C—R₂ or N; V is C—R₈; W is N, X is C—R₁₀ or N and Y isC—R₁₁; or W is N, X is C—R₁₀ and Y is C—R₁₁ or N; or X is N, W is C—R₉or N and Y is C—R₁₁; or X is N, W is C—R₉ and Y is C—R₁₁ or N; or Y isN, W is C—R₉ or N and X is C—R₁₀; or Y is N, W is C—R₉ and X is C—R₁₀ orN; R₂, R₈, R₉, R₁₀ and R₁₁ each, independently of one another, ishydrogen, amino, amido, cyano, nitro, halogen, alkyl, alkenyl, alkynyl,cycloalkyl, hydroxyalkyl, haloalkyl, alkylthio, haloalkylthio, arylthio,alkoxy, phenoxy, alkoxyalkoxy, cycloalkyloxy, haloalkoxy, alkylcarbonyl,haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,alkylamino, di(alkyl)amino, alkylcarbonylamino, alkylaminoalkoxy,dialkylaminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl,formyl, HO₂C—, alkyl-O₂C—, unsubstituted or substituted aryl orunsubstituted or substituted phenoxy, whereby the substituents may eachbe independent of one another and are selected from the group consistingof cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio,arylthio, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl and haloalkylsulfonyl;R₃, R₄ and R₅ each, independently of one another, is hydrogen, halogen,alkyl, hydroxyalkyl, alkylthioalkyl, haloalkyl, alkyloxyalkyl,alkylsulfinylalkyl, alkylsulfonylalkyl, alkylsulfonyloxyalkyl;unsubstituted or substituted cycloalkyl, wherein the substituents mayeach be independent of one another and are selected from the groupconsisting of halogen and alkyl; or unsubstituted or substituted phenyl,whereby the substituents may each be independent of one another and areselected from the group consisting of cyano, nitro, halogen, alkyl,haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy,alkylcarbonyl, haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkylamino and di(alkyl)amino; or R₄and R₅ together with the carbon to which they are attached form acycloalkyl ring; R₆ is hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl,alkylthiocarbonyl or unsubstituted or substituted benzyl, whereby thesubstituents may each be independent of one another and are selectedfrom the group consisting of cyano, nitro, halogen, alkyl, haloalkyl,alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl,haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkylamino and di(alkyl)amino; R₇ is hydrogen, alkyl,alkoxyalkyl, alkylcarbonyl, alkylthiocarbonyl or unsubstituted orsubstituted phenyl wherein the substituents may each be independent ofone another and are selected from the group consisting of cyano, nitro,halogen, alkyl, haloalkyl, phenyl, phenoxy, alkylthio, haloalkylthio,arylthio, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonylalkylamino and di(alkyl)amino; unsubstituted or substituted hetaryl,wherein the substituents may each be independent of one another and areselected from the group consisting of cyano, nitro, halogen, alkyl,haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy,alkylcarbonyl, haloalkylcarbonyl, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, alkylamino and di(alkyl)amino; or unsubstituted orsubstituted naphthyl or quinolyl, wherein the substituents may each beindependent of one another and are selected from the group consisting ofcyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio,arylthio, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, alkylamino anddi(alkyl)amino; Z is a direct bond, C(O), C(S) or S(O)_(p); a is 1, 2 or3; p is 0, 1 or 2; or salts thereof.
 2. Thearyloazol-2-yl-cyanoethylamine of claim 1, wherein R₂, R₈, R₉, R₁₀ andR₁₁ each, independently of one another, is hydrogen, amino, amido,cyano, nitro, halogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₃-C₇-cycloalkyl, hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio arylthio, C₁-C₆-alkoxy, phenoxy,C₁-C₆-alkoxy-C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino,di(C₁-C₆-alkyl)amino, C₁-C₆-alkylcarbonylamino,C₁-C₆-alkylamino-C₁-C₆-alkoxy, di-C₁-C₆-alkylamino-C₁-C₆-alkoxy,C₁-C₆-alkylamino-C₁-C₆-alkyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl,amino-C₁-C₆-alkyl, formyl, HO₂C—, C₁-C₆-alkyl-O₂C—, unsubstituted orsubstituted aryl or unsubstituted or substituted phenoxy, whereby thesubstituents may each be independent of one another and are selectedfrom the group consisting of cyano, nitro, halogen, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl and halo-C₁-C₆-alkylsulfonyl; R₃, R₄ and R₅ each,independently of one another, is hydrogen, halogen, C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylsulfinyl-C₁-C₆-alkyl,C₁-C₆-alkylsulfonyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyloxy-C₁-C₆-alkyl;unsubstituted or substituted C₃-C₇-cycloalkyl, wherein the substituentsmay each be independent of one another and are selected from the groupconsisting of halogen and C₁-C₆-alkyl; or unsubstituted or substitutedphenyl, whereby the substituents may each be independent of one anotherand are selected from the group consisting of cyano, nitro, halogen,C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio,arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, halo-C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino anddi(C₁-C₆-alkyl)amino; or R₄ and R₅ together with the carbon to whichthey are attached form a cycloalkyl ring; R₆ is hydrogen, C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylthiocarbonylor unsubstituted or substituted benzyl, whereby the substituents mayeach be independent of one another and are selected from the groupconsisting of cyano, nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,halo-C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino and di(C₁-C₆-alkyl)amino; R₇is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl,C₁-C₆-alkylthiocarbonyl or unsubstituted or substituted phenyl whereinthe substituents may each be independent of one another and are selectedfrom the group consisting of cyano, nitro, halogen, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, phenyl, phenoxy, C₁-C₆-alkylthio,halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, halo-C₁-C₆-alkylsulfonylC₁-C₆-alkylamino and di(C₁-C₆-alkyl)amino; unsubstituted or substitutedhetaryl, wherein the substituents may each be independent of one anotherand are selected from the group consisting of cyano, nitro, halogen,C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio,arylthio, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino and di(C₁-C₆-alkyl)amino; orunsubstituted or substituted naphthyl or quinolyl, wherein thesubstituents may each be independent of one another and are selectedfrom the group consisting of cyano, nitro, halogen, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino and di(C₁-C₆-alkyl)amino; Z is adirect bond, C(O), C(S) or S(O)_(p); a is 1, 2 or 3; and p is 0, 1 or 2.3. The aryloazol-2-yl-cyanoethylamine of claim 2, wherein R₂, R₈, R₉,R₁₀ and R₁₁ each, independently of one another, is hydrogen, amino,amido, cyano, nitro, halogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₃-C₇-cycloalkyl, hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio arylthio, C₁-C₆-alkoxy, phenoxy,C₁-C₆-alkoxy-C₁-C₆-alkoxy, C₃-C₇-cycloalkyloxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl,halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino,di(C₁-C₆-alkyl)amino, C₁-C₆-alkylcarbonylamino,C₁-C₆-alkylamino-C₁-C₆-alkoxy, di-C₁-C₆-alkylamino-C₁-C₆-alkoxy,C₁-C₆-alkylamino-C₁-C₆-alkyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl,amino-C₁-C₆-alkyl, formyl, HO₂C—, C₁-C₆-alkyl-O₂C—, unsubstituted orsubstituted aryl or unsubstituted or substituted phenoxy, whereby thesubstituents may each be independent of one another and are selectedfrom the group consisting of cyano, nitro, halogen, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl and halo-C₁-C₆-alkylsulfonyl; R₃, R₄ and R₆ are H;R₅ is methyl; R₇ is unsubstituted or substituted phenyl wherein thesubstituents may each be independent of one another and are selectedfrom the group consisting of cyano, nitro, halogen, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,halo-C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkylamino and di(C₁-C₆-alkyl)amino;unsubstituted or substituted hetaryl, wherein the substituents may eachbe independent of one another and are selected from the group consistingof cyano, nitro, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkylthio, halo-C₁-C₆-alkylthio, arylthio, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkylcarbonyl,C₁-C₆-alkylsulfinyl, halo-C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-alkylamino and di(C₁-C₆-alkyl)amino; Z is C(O); and a is
 1. 4. Thearyloazol-2-yl-cyanoethylamine of claim 1, wherein R₃, R₄ and R₆ arehydrogen; R₅ is hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,C₁-C₆-alkyloxy-C₁-C₆-alkyl, or C₁-C₆-alkylsulfonyloxy-C₁-C₆-alkyl; R₇ isunsubstituted phenyl or phenyl substituted by one or more substituentsselected from the group consisting of C₁-C₆-alkyl, halo-C₁-C₆-alkyl,phenyl, phenyloxy, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkylthio,halo-C₁-C₆-alkylthio, halo-C₁-C₆-alkylsulfinyl andhalo-C₁-C₆-alkylsulfonyl; R₂, R₈, R₉, R₁₀ and R₁₁ each, independently ofone another, is hydrogen, halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, cyano,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₁-C₆-alkylamino,hydroxy-C₁-C₆-alkyl, formyl, C₁-C₆-alkylamino-C₁-C₆-alkyl, HO₂C—,C₁-C₆-alkyl-O₂C— or unsubstituted or substituted phenyl wherein thesubstituents are C₁-C₆-alkyl or halo-C₁-C₆-alkyl; Z is C(O); and a is 1.5. The aryloazol-2-yl-cyanoethylamine of claim 1, wherein R₃, R₄ and R₆are hydrogen; R₅ is methyl, ethyl, butyl, CH₂OH, CH₂OCH₃, CH₂SCH₃ orCH₂OSO₂CH₃; R₇ is a phenyl substituted with butyl, CF₃, phenyl, phenoxy,OCF₃, SCF₃, SOCF₃ or SO₂CF₃; R₂, R₈, R₉, R₁₀ and R₁₁ each, independentlyof one another, is hydrogen, methyl, CH₂NH₂, CH₂N(CH₃)₂, vinyl, CH₂OH,CH(OH)CH₂OH, CO₂H, CO₂CH₃, Ph-CF₃, F, Cl, Br, CF₃, OCF₃ or CN; Z isC(O); and a is
 1. 6. The aryloazol-2-yl-cyanoethylamine of claim 1,wherein R₂ is hydrogen, Cl, methyl, methoxy, ethoxy, propoxy, butoxy,O(CH₂)₂OCH₃, or O(CH₂)₂N(CH₃)₂; R₃, R₄ and R₆ are hydrogen; R₅ ismethyl; R₇ is phenyl substituted by OCF₃, phenoxy or SCF₃; R₈, R₉ andR₁₀ each, independently of one another, is hydrogen, Cl, Br,C₁-C₆-alkyl, CF₃, nitro, amino, amido, CO₂CH₃ or NHCOCH₃; Z is C(O); anda is
 1. 7. The aryloazol-2-yl-cyanoethylamine of claim 1, wherein R₂ ishydrogen, Cl, Br or methoxy; R₃, R₄ and R₆ are hydrogen; R₅ is methyl;R₇ is phenyl substituted by OCF₃ or SCF₃; R₈, R₉, R₁₀ and R₁₁ each,independently of one another, is hydrogen, Cl, Br or methyl; Z is C(O);and a is
 1. 8. A pesticidal composition comprising a compound of claim 1and a pesticidally or veterinarily acceptable carrier.
 9. The pesticidalcomposition of claim 8 which further comprises an additional pesticidalcompound.
 10. The aryloazol-2-yl-cyanoethylamine of claim 4, wherein Wis C—R₉; X is C—R₁₀; Y is N; R₂ is hydrogen, Cl, Br or methoxy; R₃, R₄and R₆ are hydrogen; R₅ is methyl; R₇ is phenyl substituted by OCF₃ orSCF₃; R₈, R₉ and R₁₀ are independently hydrogen, Cl, Br or methyl; Z isC(O); and a is
 1. 11. The aryloazol-2-yl-cyanoethylamine of claim 1,wherein V is C—R₈; W is N; X is C—R₁₀; Y is C—R₁₁; R₂ is hydrogen, Cl,Br or methoxy; R₃, R₄ and R₆ are hydrogen; R₅ is methyl; R₇ is phenylsubstituted by OCF₃ or SCF₃; R₈, R₁₀ and R₁₁ are independently hydrogen,Cl, Br or methyl; Z is C(O); and a is
 1. 12. Thearyloazol-2-yl-cyanoethylamine of claim 4, wherein W is C—R₉; X is N; Yis C—R₁₁; R₂ is hydrogen, Cl, Br or methoxy; R₃, R₄ and R₆ are hydrogen;R₅ is methyl; R₇ is phenyl substituted by OCF₃ or SCF₃; R₈, R₉ and R₁₀are independently hydrogen, Cl, Br or methyl; Z is C(O); and a is
 1. 13.The aryloazol-2-yl-cyanoethylamine of claim 3, wherein W is N; X isC—R₁₀; and Y is C—R₁₁.
 14. The aryloazol-2-yl-cyanoethylamine of claim3, wherein W is C—R₉; X is N; and Y is C—R₁₁.
 15. Thearyloazol-2-yl-cyanoethylamine of claim 3, wherein W is C—R₉; X isC—R₁₀; and Y is N.